Parkinsonism; Causes, Symptom, Diagnosis, Treatment

Parkinsonism
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Parkinsonism (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms generally come on slowly over time. Early in the disease, the most obvious are shaking, rigidity, slowness of movement, and difficulty with walking. Thinking and behavioral problems may also occur. Dementia becomes common in the advanced stages of the disease. Depression and anxiety are also commonly occurring in more than a third of people with PD. Other symptoms include sensory, sleep, and emotional problems. The main motor symptoms are collectively called parkinsonism or a parkinsonian syndrome.

Causes of Parkinson’s Disease

  • Your genes – Researchers have identified specific genetic mutations that can cause Parkinson’s disease, but these are uncommon except in rare cases with many family members affected by Parkinson’s disease.
  • Environmental triggers – Exposure to certain toxins or environmental factors may increase the risk of later Parkinson’s disease, but the risk is relatively small.
  • The presence of Lewy bodies – Clumps of specific substances within brain cells are microscopic markers of Parkinson’s disease. These are called Lewy bodies, and researchers believe these Lewy bodies hold an important clue to the cause of Parkinson’s disease.
  • Alpha-synuclein is found within Lewy bodies – Although many substances are found within Lewy bodies, scientists believe an important one is a natural and widespread protein called alpha-synuclein (A-synuclein). It’s found in all Lewy bodies in a clumped form that cells can’t break down. This is currently an important focus among Parkinson’s disease researchers.
Parkinson disease also causes other symptoms
  • Sleep problems-  including insomnia, are common, often because people need to urinate frequently or because symptoms worsen during the night, making turning over in bed difficult. Rapid-eye-movement (REM) sleep behavior disorder commonly develops. In this disorder, the limbs, which normally do not move in REM sleep, may move suddenly and violently because people are acting out their dreams, sometimes injuring a bed partner. Lack of sleep may contribute to depression and drowsiness during the day.

  • Urination problems may occur. Urination may be difficult to start and to maintain (called urinary hesitancy). People may have a compelling need to urinate (urgency). Incontinence is common.

  • Constipation – can develop because the intestine may move its contents more slowly. Inactivity and levodopa, the main drug used to treat Parkinson disease, can worsen constipation.

  • sudden, excessive decrease in blood pressure – may occur when a person stands up (orthostatic hypotension).

  • Scales – (seborrheic dermatitis) develop often on the scalp and face and occasionally in other areas.

  • Loss of smell – (anosmia) is common, but people may not notice it.

  • Dementia –develops in about one-third of people with Parkinson disease. In many others, thinking is impaired, but people may not recognize it.

  • Depression – can develop, sometimes years before people have problems with movement. Depression tends to worsen as Parkinson disease becomes more severe. Depression can also make movement problems worse.

  • Hallucinations, delusions, and paranoia can occur, particularly if dementia develops. People may see or hear things that are not there (hallucinations) or firmly hold certain beliefs despite clear evidence that contradicts them (delusions). They may become mistrustful and think other people intend them harm (paranoia). These symptoms are considered psychotic symptoms because they represent a loss of contact with reality. Psychotic symptoms are the most common reason people with Parkinson disease are put in an institution. Having these symptoms increases the risk of dying.

Symptoms of Parkinson’s Disease

Primary symptoms include

Some secondary symptoms include

Symptom according to motor function

Motor symptoms

  • Tremor
  • Bradykinesia (slow movement)
  • Rigidity and freezing in place
  • Stooped posture
  • Shuffling gait
  • Decreased arm swing when walking
  • Difficulty rising from a chair
  • Micrographia (small, cramped handwriting)
  • Lack of facial expression
  • Slowed activities of daily living (for example, eating, dressing, and bathing)
  • Difficulty turning in bed
  • Remaining in a certain position for a long period of time

Nonmotor symptoms

Several staging systems for Parkinson’s disease exist depending upon the organization that treats and researches the disease. The Parkinson’s Foundations supports five stages.

  • Stage 1 – Symptoms are mild and do not interfere with the person’s quality of life.
  • Stage 2 – Symptoms worsen and daily activities become more difficult and take more time to complete.
  • Stage 3 – Is considered mid-stage Parkinson’s disease. The individual loses balance, moves more slowly, and falls are common. Symptoms impair daily activities, for example, dressing, eating, and brushing teeth.
  • Stage 4 – Symptoms become severe and the individual needs assistance walking and performing daily activities.
  • Stage 5 – Is the most advanced stage of Parkinson’s disease. The individual is unable to walk and will need full-time assistance with living.
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With proper treatment, most individuals with Parkinson’s disease can lead long, productive lives for many years after diagnosis. The life expectancy is about the same as people without the disease.

Diagnosis of Parkinson’s Disease

Methods to assist with the diagnosis of PD include

  • Neurological examination (including evaluation of symptoms and their severity)
  • Trial test of drugs. When symptoms are significant, a trial test of drugs (primarily levodopa ) may be used to further diagnose the presence of PD. If a patient fails to benefit from levodopa, a diagnosis of Parkinson’s disease may be questionable.
  • Computed tomography scan (also called a CT or CAT scan) – A diagnostic imaging procedure that uses a combination of X-rays and computer technology to produce horizontal, or axial, images (often called slices) of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays.
  • Magnetic resonance imaging (MRI) – A diagnostic procedure that uses a combination of large magnets, radio frequencies, and a computer to produce detailed images of organs and structures within the body.

Treatments of Parkinson’s Disease

Symptomatic drug therapy

Treatment for nonmotor symptoms

Deep brain stimulation

  • The surgical procedure of choice for Parkinson disease
  • Does not involve the destruction of brain tissue
  • Reversible
  • Can be adjusted as the disease progresses or adverse events occur
  • Bilateral procedures can be performed without a significant increase in adverse events

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
  • Modafinil should be considered for patients who subjectively experience excessive daytime somnolence
  • For insomnia, the 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 the restless-legs syndrome
  • methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)
  • The evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety, and RMD

Others treatment

General measures used to treat Parkinson disease can help people function better.

Many drugs can make movement easier and enable people to function effectively for many years. The mainstay of treatment for Parkinson disease is

Other drugs are generally less effective than levodopa, but they may benefit some people, particularly if levodopa is not tolerated or is inadequate. However, no drug can cure the disease.

Two or more drugs may be needed. For older people, doses are often reduced. Drugs that cause or worsen symptoms, particularly antipsychotic drugs, are avoided. The drugs used to treat Parkinson disease can have troublesome side effects. If people notice any unusual effects (such as difficulty controlling urges or confusion), they should report them to their doctor. They should not stop taking a drug unless their doctor tells them to.

Deep brain stimulation, a surgical procedure, is considered if people have the advanced disease but no dementia nor psychiatric symptoms and drugs are ineffective or have severe side effects.

General measures

Various simple measures can help people with Parkinson disease maintain mobility and independence:

  • Continuing to do as many daily activities as possible

  • Following a program of regular exercise

  • Simplifying daily tasks—for example, having buttons on clothing replaced with Velcro fasteners or buying shoes with Velcro fasteners

  • Using assistive  devices, such as zipper pulls and button hooks

Physical therapists and occupational therapists can help people learn how to incorporate these measures into their daily activities, as well as recommend exercises to improve muscle tone and maintain range of motion. Therapists may also recommend mechanical aids, such as wheeled walkers, to help people maintain independence.

Simple changes around the home can make it safer for people with Parkinson disease:

  • Removing throw rugs to prevent tripping

  • Installing grab bars in bathrooms and railings in hallways and other locations to reduce the risk of falling

For constipation, the following can help Consuming a high-fiber diet, including such foods as prunes and fruit juices

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  • Exercising

  • Drinking plenty of fluids

  • Using stool softeners (such as senna concentrate), supplements (such as psyllium), or stimulant laxatives (such as bisacodyl taken by mouth) to keep bowel movements regular

Difficulty swallowing may limit food intake, so the diet must be nutritious. Making an effort to sniff more deeply may improve the ability to smell, enhancing the appetite.

Levodopa/carbidopa

Traditionally, levodopa, which is given with carbidopa, is the first drug used. These drugs, taken by mouth, are the mainstay of treatment for Parkinson disease. But when taken for a long time, levodopa may have side effects and become less effective. So some experts have suggested that using other drugs first and delaying use of levodopa might help. However, evidence now indicates that the side effects and reduced effectiveness after long-term use probably occur because Parkinson disease is worsening and are not related to when the drug was begun. Still, because levodopa may become less effective after several years of use, doctors may prescribe another drug for people under 60, who will be taking drugs to treat the disease for a long time. Other drugs that may be used include amantadine and dopamine agonists (drugs that act like dopaminestimulating the same receptors on brain cells). Such drugs are used because the production of dopamine is decreased in Parkinson disease.

Levodopa reduces muscle stiffness, improves movement, and substantially reduces tremor. Taking levodopa produces a dramatic improvement in people with Parkinson disease. The drug enables many people with mild disease to return to a nearly normal level of activity and enables some people who are confined to bed to walk again.

Levodopa rarely helps people who have other disorders that can cause symptoms similar to those of Parkinson disease (parkinsonism), such as multiple system atrophy and progressive supranuclear palsy.

Levodopa is a dopamine precursor. That is, it is converted into dopamine in the body. Conversion occurs in the basal ganglia, where levodopa helps compensate for the decrease in dopamine due to the disease. However, before levodopa reaches the brain, some of it is converted to dopamine in the intestine and in the blood. Having dopamine in the intestine and blood increases the risk of side effects such as vomiting, orthostatic hypotension, and flushing. Carbidopa is given with levodopa to prevent levodopa from being converted to dopamine before it reaches the basal ganglia. As a result, there are fewer side effects, and more dopamine is available to the brain.

To determine the best dose of levodopa for a particular person, doctors must balance control of the disease with the development of side effects, which may limit the amount of levodopa the person can tolerate. These side effects include

After taking levodopa for 5 or more years, more than half the people begin to alternate rapidly between a good response to the drug and no response—called on-off effects. Within seconds, people may change from being fairly mobile to being severely impaired and immobile. The periods of mobility after each dose become shorter, and symptoms may occur before the next scheduled dose—the off effects. Also, symptoms may be accompanied by involuntary movements due to levodopa use, including writhing or hyperactivity. One of the following can be used to control the off effects for a while:

  • Taking lower, more frequent doses

  • Switching to a form of levodopa that is released more gradually into the blood (a controlled-release formulation)

  • Adding a dopamine agonist or amantadine

However, after 15 to 20 years, the off effects become hard to suppress. Surgery is then considered.

A formulation of levodopa/carbidopa can be given using a pump connected to a feeding tube inserted in the small intestine. This formulation is being studied as a treatment for people who have severe symptoms that cannot be relieved by drugs and who cannot undergo surgery. This formulation appears to greatly reduce the off times and increase the quality of life.

Other Drugs

Other drugs are generally less effective than levodopa, but they may benefit some people, particularly if levodopa is not tolerated or is insufficient.

Dopamine agonists – which act like dopamine, may be useful at any stage of the disease. They include

Because apomorphine is quick-acting, it is used to reverse the off effects of levodopa when movement is difficult to initiate. Thus, this drug is called rescue therapy. It is usually used when people freeze in place, preventing them, for example, from walking. Affected people or another person (such as a family member) can inject the drug up to 5 times a day as needed. In some countries, apomorphine is available in a formulation that can be given using a pump to people who have severe symptoms when surgery is not an option.

Rasagiline and selegiline – belong to a class of drugs called monoamine oxidase inhibitors (MAO inhibitors). They prevent the breakdown of dopamine, thereby prolonging dopamine’s action in the body. Theoretically, if taken with certain foods (such as certain cheeses), beverages (such as red wine), or drugs, MAO inhibitors can have a serious side effect called a hypertensive crisis. However, this effect is unlikely when Parkinson disease is being treated because the doses used are low and the type of MAO inhibitor used (MAO type B inhibitors), particularly rasagiline, is less likely to have this effect.

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Catechol O-methyltransferase (COMT) inhibitors – (entacapone and tolcapone) slow the breakdown of levodopa and dopamine, prolonging their effects, and therefore appear to be a useful supplement to levodopa. These drugs are used only with levodopa. Tolcapone is seldom used because rarely, it damages the liver. However, tolcapone is stronger than entacapone and may be more useful if off effects are severe or long-lasting.

Anticholinergic drugs (given for their anticholinergic effects) are effective in reducing the severity of a tremor and can be used in the early stages of Parkinson disease. Commonly used anticholinergic drugs include benztropine and trihexyphenidyl. Anticholinergic drugs are particularly useful for very young people whose most troublesome symptom is a tremor. These drugs are not used in older people because they have side effects (such as confusion, drowsiness, dry mouth, blurred vision, dizziness, constipation, difficulty urinating, and loss of bladder control) and because these drugs, when taken for a long time, increase the risk of mental decline. They may reduce tremor because they block the action of the neurotransmitter acetylcholine, and tremor is thought to be caused by an imbalance of acetylcholine (too much) and dopamine (too little).

Occasionally, other drugs with anticholinergic effects, including some antihistamines and tricyclic antidepressants, are used, sometimes to supplement levodopa. However, because these drugs are only mildly effective and because many anticholinergic effects are troublesome, these drugs are seldom used to treat Parkinson disease.

Amantadine, a drug sometimes used to treat influenza, may be used alone to treat mild Parkinson disease or as a supplement to levodopa. Amantadine probably has many effects that make it work. For example, it stimulates nerve cells to release dopamine. It is used most often to help control the involuntary movements that are side effects of levodopa.

Deprenyl

A medicine that can be given with L-DOPA, or separately, is deprenyl. Deprenyl inhibits the activity of the enzyme MAO-B, which then will slow the progression of Parkinson’s disease. Deprenyl, however, does not completely stop the degeneration of dopaminergic neurons. Deprenyl delays the time before other antiparkinson drugs, like L-DOPA, need to be used.

Tyrosine Hydroxylase

Tyrosine hydroxylase catalyzes the formation of L-DOPA, the rate-limiting step in the biosynthesis of dopamine. In other words, it is a precursor to neurotransmitters and increases plasma neurotransmitter levels of dopamine and norepinephrine. This medication should not be used when taking L-DOPA, as L-DOPA interferes with the absorption of Tyrosine.

Apomorphine

Apomorphine has also been used to treat Parkinson’s disease. It is referred to as a dopamine receptor agonist. However, it does cause severe side effects when used on its own.

mGluR4

N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is now being studied as a selective allosteric potentiator of mGluR4. Metabotropic glutamate receptor 4 (mGluR4) is a potential drug target for Parkinson’s disease. PHCCC selectively potentiated agonist-induced mGluR4 activity in cells expressing this receptor and did not itself act as an agonist. PHCCC also potentiated the effect of L-(+)-2-amino-4-phosphonobutyric acid in inhibiting transmission at the striatopallidal synapse. This is significant due to the striatopallidal synapse being proposed as a target for Parkinson’s disease treatment. This can hopefully restore balance in the basal ganglia motor circuit.

Surgery of Parkinson’s Disease

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations has declined. Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.

Surgery for PD can be divided in two main groups – lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, the globus pallidus or the subthalamic nucleus. Deep brain stimulation is the most commonly used surgical treatment, developed in the 1980s by Alim Louis Benabid and others. It involves the implantation of a medical device called a neurostimulator, which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD with motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems. Other, less common, surgical therapies involve the intentional formation of lesions to suppress overactivity of specific subcortical areas. For example, pallidotomy involves surgical destruction of the globus pallidus to control dyskinesia.

References

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