PARKINSON'S DISEASE
Parkinson’s Disease (PD) is a common disease. It’s a degenerative disorder of the central nervous system first described by James Parkinson in 1817.
The natural history of the disease is of interest. As a rule, it begins between 40 and 70 years of age, with the peak age of onset in the sixth decade. It is infrequent before 30 years of age, and men are slightly more affected than women.
CLINICAL FEATURES
A tetrad of hypo- and bradykinesia(slowness), resting tremor, postural instability(imbalance), and rigidity(stiffness) are the core features of Parkinson disease. These are evident as expressionless face, poverty and slowness of voluntary movement, “resting” tremor, stooped posture, axial instability, rigidity, and festinating gait.
The early symptoms may be difficult to appreciate and are often overlooked by family members because they evolve slowly and tend to be attributed to the natural changes of aging.
Tremor
The characteristic tremor, which usually involves a hand, is often listed as the initial sign. In 20 to 25 percent of cases the tremor is mild and intermittent or evident in only one finger or one hand not used in voluntary movement (hence the term resting tremor).
One side of the body is typically involved before the other, and the classic tremor then remains asymmetrical as the illness advances.
Rigidity
Rigidity and hypertonous may not be important early findings. These features tend to appear in the more advanced stages of the disease. Once rigidity develops, it is constantly present, and sometimes associated with cog wheel phenomenon.
Bradykinesia
Bradykinesia refers to slowness in both the initiation and execution of movement. The quality of volitional and postural movements are affected. The patient is slow and ineffective in attempts to deliver a quick hard blow; he cannot complete a quick (ballistic) movement.
Alternating movements, at first successful, if repeated become progressively impeded and finally are blocked completely. Also, the patient has difficulty in executing two motor acts simultaneously. In the extreme degree of bradykinesia, patient becomes akinetic – i.e. the patient is motionless.
As the disorder of movement worsens, all customary activities
show the effects. Handwriting becomes small (micrographia), tremulous,
and cramped. The voice softens and the speech seems hurried and monotonous and mumbling: the voice becomes less audible and finally the patient only whispers.
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The consumption of a meal takes an inordinately long time. Each morsel of food must be swallowed before the next bite is taken. Walking becomes reduced to a shuffle. Falls do occur, but surprisingly infrequently given the degree of postural instability. Gait is typically improved by sensory guidance, as by holding the patient at the elbow. Obstacles
such as door thresholds have the opposite effect, at times causing the patient to “freeze” in place. Difficulty in turning over in bed is a characteristic feature as the illness advances, but the patient rarely volunteers this information; several of our patients have fallen out of bed at a frequency that suggests a connection to their reduced mobility. Shaving or applying lipstick becomes difficult, as the facial muscles become more immobile and rigid.
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As noted above, these various motor impediments and tremors characteristically begin in one limb (more often the left) and spread to one side and later to both sides, until the patient is quite helpless.
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​In addition to movement-related (“motor”) symptoms, Parkinson’s symptoms may be unrelated to movement (“non-motor”).People with PD are often more impacted by their non-motor symptoms than motor symptoms. Examples of non-motor symptoms include: apathy, depression, constipation, sleep behavior disorders, loss of sense of smell and cognitive impairment. At times, Parkinson disease is complicated by a dementia, in about 10 to 15 percent patients.
The incidence increases with advancing age, approaching 65 percent in Parkinson patients above 80 years of age, but it may be disabling even in patients in their late fifties. The overall course of the disease is quite variable. In the majority of patients, the mean period of time from inception of the disease to a chair bound state is 7.5 years, but again, with a wide range. On the other hand, as many as one-third of cases are relatively mild and such patients may remain stable for 10 years or more.
Initial symptoms in patients with Parkinson disease
(Adapted from Hoehn and Yahr’s study of 183 idiopathic cases)
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Tremor 70%
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Gait disturbance 11%
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Stiffness 10%
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Slowness 10%
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Muscle aches 8%
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Loss of dexterity 7%
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Handwriting disturbance 5%
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Depression, nervousness, other psychiatric disturbance 4%
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Speech disturbance 3%
SCALES USED BY THE CLINICIANS TO GAUGE THE PROGRESSION OF THE DISEASE
Modified Hoehn and Yahr scale
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Hoehn and Yahr stages follow a simple rating scale, first introduced in 1967. Clinicians use it to describe how motor symptoms progress in Parkinson's Disease.
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On this scale, 1 and 2 represent early-stage, 2 and 3 mid-stage, and 4 and 5 advanced stage Parkinson's.
Stage One
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During this initial stage, the person has mild symptoms that generally do not interfere with daily activities. Tremor and other movement symptoms occur on one side of the body only. Changes in posture, walking and facial expressions occur.
Stage Two
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Symptoms start getting worse. Tremor, rigidity and other movement symptoms affect both sides of the body. Walking problems and poor posture may be apparent. The person is still able to live alone, but daily tasks are more difficult and lengthy.
Stage Three
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Considered mid-stage, loss of balance and slowness of movements are hallmarks. Falls are more common. The person is still fully independent, but symptoms significantly impair activities such as dressing and eating.
Stage Four
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At this point, symptoms are sever and limiting. It's possible to stand without assistance, but movement may require a walker. The person needs help with activities of daily living and is unable to live alone.
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Stage Five
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This is the most advanced and debilitating stage. Stiffness in the legs may make it impossible to stand or walk. The person requires a wheelchair or is bedridden. Around-the-clock nursing care is required for all activities. The person may experience hallucinations and delusions. The Parkinson's community acknowledges that there are many important non-motor symptoms as well as motor symptoms.
DIAGNOSIS​
Early in the course of Parkinson disease, when only a slight asymmetry of stride or an ineptitude of one hand is present and the tremor has yet to appear and the impart the unmistakable stamp of the disease, a number of small signs already mentioned may be helpful in diagnosis. These include a reduced blink rate, a lack of arm swing, a tendency for rapid alternating movements to be slowed and perceptible rigidity of one arm when the opposite limb is occupied in a motor task such as tracing circles in the air.
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The two main difficulties in diagnosis are to distinguish typical Parkinson disease from the many parkinsonian syndromes caused by other degenerative diseases and by medications or toxins and to distinguish the Parkinson tremor from other types. It is worth noting that Parkinson disease is far more common than any of the syndromes that resemble it. Bradykinesia and rigidity of the limbs and axial musculature are symptoms shared with other forms of parkinsonism, but only in Parkinson disease does one see an early sign of "resting" alternating tremor that is more prominent in one arm.
DIFFERENTIAL DIAGNOSIS
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The typical signs of Parkinson disease, when present in their entirety, impart an unmistakable clinical picture. When not all signs are evident, there is no alternative but to re-examine the patient at several-month intervals until it is clear that Parkinson disease is present or until the signature of another degenerative process becomes evident (e.g. vertical gaze impairment in progressive spranacular palsy; dysautonomia with fainting, bladder, or vocal cord signs in striatonigral degeneration; early and rapidly evolving dementia or psychosis in Lewy body disease, or apraxia in corticobasal ganglionic degeneration or Multiple System Atrophy).
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A beneficial response to levodopa or a dopamine agonist also gives a reasonable although not entirely conclusive indication of the presence of Parkinson disease. The other parkinsonian syndromes are for most part unchanged by the drug.
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The rapid onset of the Parkinson syndrome, especially in conjunction with other medical diseases, should always raise the suspicion of drug effects; phenothiazines, haloperidol, and the nuroleptics pimozide and metoclopramide, used at times as antiemetics, all cause a slight masking of the face, stiffness of the trunk and limbs, lack of arm swing, fine tremor of the hands, and mumbling speech. Even the newer antipsychotic medications, favored specifically because of a putative lack of extrapyramidal effects, may be at fault.
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All in all, if one adheres to the strict definition of Parkinson disease---bradykinesia, "resting" tremor, postural changes and instability, cogwheel rigidity, and response to L-dopa---errors in diagnosis are few.
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Despite this, the diagnosis of PD can be inaccurate in around 25 percent of patients. The reasons are that about this number of Parkinson patients fail to display the characteristic tremor and about 10 percent are said to not respond to L-dopa.
TREATMENT
Although there is no current treatment that halts or reverses the neuronal degeneration underlying Parkinson's disease, methods are now available that afford considerable relief from symptoms.
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Treatment can be medical or surgical, although reliance is placed mainly on drugs, particularly on L-dopa.
MEDICAL MANAGEMENT
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Medical management remains the first-line of treatment for patients diagnosed with PD.
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A person with Parkinson's disease (PD) must be individually evaluated to determine which drug or combination of medications is best for them. Dosages vary based on the person's needs and metabolism.
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Since most symptoms of Parkinson's disease (PD) are caused by a lack of dopamine in the brain, many drugs for PD are aimed at either temporarily replenishing dopamine or mimicking the action of dopamine (dopaminergic medications). They generally help reduce muscle rigidity, improve speed and coordination of movement and lessen tremor.
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Medication is only part of the overall treatment plan for combating PD. Exercise and complementary therapies are equally important.
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Caution: PD medications may have interactions with certain foods, other medications, vitamins, herbal supplements, over-the-counter cold pills and other remedies. Anyone taking a PD medication should talk to their doctor and pharmacist about potential drug interactions.
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Several effective drugs that are being used
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L-Dopa & L-Dopa-Modifying Drugs (Carbidopa, Entacapone,Tolcapne).
These are unquestionably the most effective agent for the treatment of Parkinson's disease. -
Dopamine agonist (Ropinirole, Pramipexole)
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Anticholinergic agents (Benztropine, Trihexyphenydyl)
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Glutamate agonist (Amantidine)
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Majority of the patients respond to these drugs and their symptoms remain well controlled for many years.
Challenges in medical management of advanced disease
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The most troublesome effects of L-dopa as the disease advances, usually after several years of treatment, are
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an end of dose reduction in efficacy and
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the more precipitous "on-off" phenomenon
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the induction of involuntary "dyskinetic" movements
A decline in efficacy after the usual 2 to 4 hours may be treated by more frequent dosing or the addition of a COMT inhibitor.
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The on-off phenomenon is a rapid sometimes unpredictable change in the patient, in a matter of minutes or from one hour to the next, from a state of relative freedom from symptoms to one of complete or nearly complete immobility. Both dyskinesias and severe "off" periods eventually appear in about 75 percent of patients within 5 years. Above a certain daily dose level of L-dopa, which varies from patient to patient, very few patients escape these effects, forcing an increased frequency of administration and usually a reduction in dosage.
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If involuntary movements (dyskinesias) are induced by relatively small doses of L-dopa, the problem may be suppressed to some extent by the addition of direct-acting dopaminegric agents or by the concurrent administration of amantadine. The use of lower doses of long-action preparation of L-dopa may also be helpful in reducing dyskinesias.
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The onset of psychiatric symptoms coincident with the use of L-dopa may also present problems and is to be expected eventually in 15 to 25 percent of patients, particularly in the elderly. Depression, delusional thinking may also occur in these circumstances. Excitement and aggressiveness appear in a few.
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An important note of warning: Anticholinergic agents or L-dopa should not be discontinued abruptly in advanced Parkinson disease. If this is done, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome, sometimes fatal, has been induced by such withdrawal. Reducing the medication dose over a week or so is usually adequate.
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With progressive loss of nigral cells, there is an increasing inability to store L-dopa and periods of drug effectiveness become shorter. In some instances, the patient becomes so sensitive to L-dopa that as slight an excess as 50 to 100 mg will precipitate choreoathetosis; if the dose is lowered by the same amount, the patient may develop disabling rigidity. With the end-of-dose loss of effectiveness and on-off phenomenon, which with time become increasingly frequent and unpredictable, the patient may experience pain, respiratory distress, akathisia, depression, anxiety, and even hallucinations. Some patients function quite well in the morning and much less in the afternoon, or vice versa. In such cases, and for end-of-dose and on-off phenomena, one must titrate the dose of L-dopa and utilize more frequent doses during the 24-h day; combining it with other drugs like a dopamine agonist or long-acting preparation may be helpful. Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications may reduce the on-off phenomenon.
Apomorphine injections and pumps
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Apomorphine is a strong dopamine agonist. They stimulate nerve cells and thereby help to reduce the symptoms of Parkinson's disease. Unlike other dopamine agonist, apomorphine is given by injection or continuous infusion, using a pump.
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It is usually used for more advanced Parkinson's, when a person's symptoms no longer respond well to oral drug treatments. Apomorphine doesn't help everyone manage their Parkinson's symptoms, and it may not replace oral medications entirely.
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Apomorphine may be suggested in patients who
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have sudden and unpredictable changes in symptoms
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have severe "off" periods that aren't controlled by other Parkinson's medications, or
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have severe swallowing difficulties and cannot take medication orally.
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Advantages of apomorphine
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Apomorphine injections can act as a rescue treatment (Works within 5-10 min, useful to treat sudden "off" period).
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Fewer "off" periods (Continuous infusions over months can reduce the number of "off" periods).
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Disadvantages of apomorphine
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Only available as an injection or infusion (Injection sites can become sore and irritated).
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Short acting (Necessitates frequent injections or infusions).
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Side effects (Nausea, vomiting, hypotension, drowsiness/sudden onset of sleep, hallucinations, delusions, impulsive and compulsive behavior)
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Low-protein diet
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Based on the notion that alimentary-derived amino acids antagonize the clinical effects of L-dopa, the use of a low-protein diet has been advocated as a means of controlling the motor fluctuations.
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Symptoms can sometimes be reduced by the simple expedient of eliminating dietary protein from breakfast and lunch. Moreover, this dietary regimen may permit the patient to reduce slightly the total daily dose of L-dopa. Such dietary manipulation is worth trying in appropriate patients; it is not harmful, and most of our patients with advanced disease who have persisted with this diet have reported improvement in their symptoms or an enhanced effect of L-dopa.
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SURGICAL MANAGEMENT
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Deep Brain Simulation
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Deep brain stimulation (DBS) involves applying high-frequency electrical stimulation to a specific target in the subcortical structures.
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Alim Louis Benabid (Neurosurgeon) and Pierre Pollack (Neurologist) were the first people to do DBS in 1987 in Grenoble, France.
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Alim Louis Benabid (Neurosurgeon)
Pierre Pollack (Neurologist)
Deep brain stimulation (DBS) surgery was first approved in 1998 to treat Parkinson's disease (PD) tremor, then in 2002 for the treatment of advanced Parkinson's symptoms. More recently, in 2016, DBS surgery was approved for the earlier stages of PD - for people who have had PD for at least four years and have motor symptoms not adequately controlled with medication. It is now widely accepted as an effective, safe and standard treatment worldwide.
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The Procedure - Involves placing a thin metal electrode into one of several possible brain targets and attaching it to a computerized pulse generator, which is implanted under the skin in the chest below the clavicle.
In DBS surgery, electrodes are inserted into a specific area of the brain (generally the subthalamic nucleus STN or the Globus pallidus GPi), using MRI (magnetic resonance imaging) and recordings of brain cell activity during the procedure. This is the part of the procedure where the patient is awake. A second procedure is performed under General Anesthesia (GA) to implant an IPS, impulse generator battery (like a pacemaker). The IPG is placed under the collarbone. The IPS provides an electrical impulse to a part of the brain involved in motor function.
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It is most effective for people who experience disabling tremors, wearing-off spells and medication-induced dyskinesias. Although DBS significantly improves the quality of life in PD patients, it is not a cure and it does not slow PD progression. It gives a good quality of life for 10-15 years depending on the age and stage of PD when DBS was performed. It may not be right for every patient with PD. It does not improve speech or swallow issues, thinking problems or gait freezing.
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Like all brain surgeries, DBS carries a small (1-3%) risk of infection, stroke, bleeding or seizures. DBS surgery may be associated with reduced clarity of speech. A small number of people with PD have experienced cognitive decline after DBS surgery. Those who undergo DBS surgery are given a controller to turn the device on or off.
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DBS does not damage health brain tissue or destroy nerve cells. Instead, the procedure interrupts problematic electrical signals from targeted areas in the brain.
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It is important that a person with PD considering DBS surgery be informed about the procedure and be realistic in his or her expectations.
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Most people after undergoing DBS, experience considerable reduction of their PD symptoms and can be greatly reduce their medications. The amount of reduction varies from person to person.
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Ideal PD Candidate for DBS
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Person with PD symptoms for at least five years.
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Person continuing to have a good response to PD medications, especially carbidopa/levodopa, although the duration of response may be insufficient (Levodopa responsive).
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Person in the age group of 40-70 years.
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Person having "on/off" fluctuations despite regular medication dosing.
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Person unable to tolerate PD medications due to side effects.
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Person with tremor that is not well controlled with medication.
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Person having severe dyskinesias.
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Person should be cognitively intact.
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Overall complications < 5% and can be procedure related (hemorrhage that may be silent or symptomatic, transient confusion, infection), device related (breakage of leads), stimulation related (usually eliminated by adjusting stimulation settings).
DUOPA (Source: Parkinson's Foundation)
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Duopa therapy is a form of carbidopa/levodopa delivered in gel form - called enteral suspension - rather than a pill. It is used to treat the motor symptoms of PD.
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Before you can start Duopa, you need surgery to make a small hole ( called a "stoma") in your stomach wall to place a tube in your intestine. A pump then delivers Duopa directly to your intestine through this tube.
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Duopa uses the same active ingredients as orally-administered carbidopa/levodopa, but is designed to improve absorption and reduce "off" times by delivering the drug directly to the small intestine.
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Who is it for?
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Dupa therapy is approved for use in people with advanced Parkinson's disease who respond well to levodopa. You might be a good candidate for Duopa therapy if you experience daily motor fluctuations with another class of medication, such as dopamine agonists or MAO-B inhibitors.
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Things to consider
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Gel carbidopa/levodopa has the same potential side effects as oral carbidopa/levodopa. Side effects include, but are not limited to, nausea, orthostatic hypotension, dyskinesia, dry mouth, constipation, confusion and hallucinations.
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Like any surgery, the procedure carries risks, as does use of the device that delivers the drug. These include movement or dislocation of the tube, infection, redness at the insertion point, bleeding, air or infection in the abdominal cavity and pump failure.
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The drug is contraindicated for those taking non-selective monoamine oxidase (MAO) inhibitors.
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Three components of Duopa therapy​
PEG-J Tube
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This is how the medications goes into your body, directly to the intestine. To clean the tubing and prevent blockages, it should be flushed with a syringe before and after every pump use. Routine care will vary depending on the type of PEG-J tubing used.
Cassette
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The cassette contains the gel carbidopa/levodopa. A new cassette must be used daily. A cassette can be used for up to 16 hours a day. Discard any leftover medication that is not used. Each cassette contains 2,000 mg of levodopa. Some people may need two cassettes in a day. Cassettes must be stored in the refrigerator. Cassettes, along with other supplies, are shipped directly from specialty pharmacy.
Duopa Pump
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The pump is specifically programmed for your individuals needs. Pump settings include:
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Morning dose: A large amount of medication that is given in the morning to get an ideal "on" state, before switching to a lower continuous dose the rest of the day.
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Continuous dose: Medication is infused continuously at the same hourly rate to help you maintain the ideal "on" state and help prevent bothersome motor fluctuations.
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Extra dose: As-needed doses may be available to control unexpected "off" time.
Ablative / Lesioning Procedure
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Lesioning can be done either by Radiofrequency ablation (RFA) / Focused Ultrasound (FUS). FUS is still not available in India.
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This involves the stereotactic placement of lesions (destroying a specific area) in either the globus pallidus (pallidotomy), ventrolateral thalamus (thalamotomy), or subthalamic nucleus (subthalamotomy), contralateral to the side of the body chiefly affected.
The best results were obtained in relatively young patients, in whom unilateral tremor or rigidity rather than akinesia were predominant.
Due to the irreversibility of these procedures and risks of permanent deficits these procedures are not commonly done today.
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OTHER ANCILLARY TREATMENTS
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Finally, in the management of the patient with Parkinson disease, one must not neglect the maintenance of optimum general health and neuromuscular efficiency by a planned program of exercise, activity and rest; expert physical therapy and exercises such as those performed in yoga may be of help in achieving these ends. Sleep may be aided by the soporific antidepressants. Postural imbalance and falls can be greatly mitigated by the use of a cane or walking frame. A number of excellent exercise programs have been devised specifically for patients with Parkinson disease, and measures such as massage and yoga have their advocates.
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Our position has that any activity that keeps the patient active and committed is of great value.
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Speech exercises help the motivated patient. Focal dystonias of the foot are partially treatable with local injections of botulinum toxin. In addition, the patient often needs a great deal of emotional support in dealing with the stress of the illness, in comprehending its nature, and in carrying an courageously in spite of it.
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