Parkinson's Disease

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What Is Parkinson’s Disease?

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Parkinson's disease (PD) is a common neurodegenerative disorder, affecting about one percent of the population over the age of 60 years. While the typical age at onset is in the sixth decade of life (average 55 years), about five percent of patients with PD have onset of their symptoms before age 40 (“young-onset PD”) and some may have onset even in childhood (“juvenile PD”). PD is 1.5 to 2 times as common in men as in women. PD is a chronic, progressive disorder of the nervous system that affects movement. It develops gradually and is commonly manifested by tremor, stiffness, slowness of movement, and gait and balance difficulties. Although there is no cure for PD, medications may markedly improve the symptoms of the disease.

Diagnosis

The symptoms and signs of PD vary from person to person. Early signs may be mild and go unnoticed. The symptoms commonly begin on one side of the body and usually remain worse on that side when the symptoms begin to affect both sides. There are a variety of symptoms that can be described as motor (pertaining to movement) and non-motor that will be described below.

Motor Symptoms

Tremor (typically present at onset in one hand at rest but may also include action, postural and re-emergent tremor, may involve all 4 limbs but almost never head or voice)
Slowed movements (bradykinesia)
Stiffness (rigidity)
Impaired posture and balance
Reduced automatic movements (blinking, smiling, arm swing with walking)
Lack of facial expression (hypomimia or “masked facies”)
Small handwriting (micrographia)
Speech changes (low volume, slurred speech)

Neurologists examine for the “cardinal features” of PD when the concern for the disease exists. These cardinal features include tremor, slowness of movement (bradykinesia), stiffness (rigidity), and loss of balance (postural instability). One of the most common presenting features of PD is an asymmetric tremor that is present while the affected limb is at rest. Some patients with PD, when carefully queried, admit long standing tremor in the hands, head, voice and other body parts (often undiagnosed “essential tremor” or ET) years before the onset of the rest tremor, typical of PD. Thus some patients may have both ET and PD (ET-PD syndrome) Other typical symptoms of PD include loss of normal facial expression (hypomimia), low volume of speech (hypophonia), and slurred speech (dysarthria). Walking can become problematic for PD patients and may involve shuffling, using short steps, and difficulty initiating gait or feeling as if the feet are glued to the floor (freezing). One’s posture may become stooped and problems with balance (loss of postural reflexes) may lead to increased risk for falls. It may also become difficult to write and the handwriting may become smaller (micrographia).

Non-motor Symptoms

It is now well recognized that PD is a complex disorder with a diverse range of symptoms that include cognitive, psychiatric, and non-motor features in addition to the motor symptoms described above. Some of these non-motor symptoms can occur years or even decades before the classic motor symptoms become noticeable (“prodromal PD”). Non-motor symptoms become more prominent as the course of Parkinson’s disease progresses and can be a major quality of life determinant.

These symptoms may include the following:

Sleep disturbances (acting out dreams due to REM Behavioral Disorder or RBD)
Mood disorders (depression, anxiety and apathy)
Fatigue
Loss of sense of smell
Loss of sense of taste
Constipation
Urinary dysfunction
Orthostatic hypotension (lightheadedness with standing due to a drop in blood pressure)
Excessive sweating
Excessive salivation
Pain and sensory symptoms
Psychosis and hallucinations
Cognitive dysfunction and dementia

Sleep difficulty can present early in PD or even before someone is diagnosed. Patients may experience insomnia, daytime sleepiness, restless leg syndrome (RLS), and rapid eye movement sleep behavior disorder (RBD). Common causes of frequent awakenings during sleep in PD include increased urinary frequency, cramps, vivid dreams or nightmares and pain, and difficulty turning in bed. RLS is a movement disorder characterized by an urge to move the limbs necessitating voluntary leg movement or getting out of bed to walk in order to temporarily relieve the unpleasant sensation. It occurs mainly at nighttime and emerges or worsens with prolonged rest such as sitting in a car or in an airplane. It is not clear whether RLS is more common in patients with PD. RBD, another common sleep disturbance in PD, is manifested by acting out of dreams, manifested by scream out and flail their arms and legs in punching, fighting and kicking motions that may result in hitting sleep partner, self-injury or even falling out of bed.

A variety of "autonomic" nervous system problems can be affected in PD. The autonomic nervous system is the part of the nervous system that helps regulate the internal organs, including the blood vessels, heart, stomach, bladder, genitals, and the sweat, salivary, and digestive glands. Symptoms that can arise from autonomic nervous system dysfunction include orthostatic hypotension (lightheadedness when standing due to a drop in blood pressure upon standing), urinary dysfunction such as urinating more frequently, sudden strong urges to urinate, and urinary incontinence, constipation, swallowing difficulty (dysphagia), excessive sweating, and erectile dysfunction.

Painful sensory symptoms are among the most troublesome non-motor symptoms in patients with both early and late-stage PD. The pain can be burning, lancinating, or tingling and can be localized to different body areas including the face, joints, abdomen, and genitals. Mood can become adversely affected and it is important to monitor for signs of depression and anxiety. Depression is the most common psychiatric disturbance seen in PD and about 50% of PD patients experience depressive symptoms. Although it is generally mild to moderate in severity, depressive symptoms may have a negative impact on motor disability and lead to reduced quality of life. Anxiety is the next most frequent mood disturbance in PD and may occur in about 30% of patients. Depression and anxiety may occur together and may also fluctuate in severity depending on “on-off” fluctuations (described in more detail in the therapy section).

Cognitive decline is relatively common in advanced stages of PD and may evolve into PD-related dementia. PD dementia may cause problems with attention and short term memory, speaking and communicating, problem-solving, and visuospatial orientation.

Prognosis

As PD progresses, the symptoms typically worsen and will require increasing doses of medications or adding additional medications to help appropriately treat symptoms. Over time, higher doses of levodopa are needed to obtain satisfactory therapeutic benefit. As time progresses, many patients (at least 50% in 5 years of levodopa treatment) develop abnormal involuntary movements called, “dyskinesias.” Dyskinesias can manifest as a variety of movements but commonly occur as head bobbing, body swaying, writhing limb movements, and abnormal muscle posturing called dystonia. When dyskinesias occur, they commonly begin when levodopa levels are higher and then resolve when levodopa wears off. Not all patients develop dyskinesias with levodopa therapy. Risk factors for levodopa-induced dyskinesias include earlier age of onset of PD, longer duration of disease, longer duration of levodopa treatment, female sex, and possibly genetic factors.

Patients may begin to appreciate a “wearing-off” effect of medication. The PD symptoms experienced when the medication is worn off are often referred to as the “OFF” symptoms. When the medication “kicks in” and patients appreciate the symptomatic benefit of the medication, it is referred to as the “ON” period. As PD progresses, patients may experience less ON time and more OFF time, referred to as “motor fluctuations,” which can usually be addressed with medication adjustments.

Because of concerns about experiencing these motor fluctuations and dyskinesias as a possible complication of levodopa therapy it is often recommended to use levodopa therapy at the “lowest effective dose” when the symptoms of PD begin to interfere with the performance of activities of daily living or work.

In most cases, the diagnosis is based on the clinical features and examination by an experienced clinician. There is no blood test for PD, although some genetic forms of parkinsonism can be diagnosed by a DNA test. Sometimes, a dopamine transporter scan (DaTscan) is ordered which can help show a loss of dopamine in the deeper structures of the brain (basal ganglia). This can help differentiate between PD and other diseases that can resemble PD (atypical or secondary parkinsonism). More recently, a skin biopsy, looking for a protein called alpha synuclein, which accumulates in the brains of patients with PD. There are many other biomarkers that have been found to reliably differentiate between PD and other parkinsonian conditions, including CSF and blood assays for alpha synuclein, but these are currently used more in research setting rather than as diagnostic tests.

Although PD is a progressive disease, it does not significantly alter life expectancy. Even though the symptoms can affect activities of daily living, interfere with work, and may adversely impact the quality of life, the prognosis varies markedly from one individual to another. The presence of tremor, rather than gait and balance problems, as the initial or dominant symptom often suggests a favorable prognosis. Thus “tremor-dominant PD” and postural-instability-gait disorder (PIGD) form of PD have been identified as two major subtypes of PD; the PIGD subtype having worse prognosis than the tremor-dominant subtype.

Cause

Although the cause (etiopathogenesis) of PD is still not completely understood, remarkable progress has been made in our knowledge about the mechanisms of neuronal cell loss (neurodegeneration). Many of the symptoms of PD are due to the reduction of a chemical in the brain called dopamine. The symptoms of PD start when there is about 60 percent loss of dopamine-producing neurons in a part of the brain called the substantia nigra. There is a growing body of evidence that shows these neurons die, in part, as a result of an abnormal accumulation of cellular proteins (such as alpha synuclein) that damage neurons and impair their ability to produce dopamine.

Dopamine is needed to act on other deep brain structures ("basal ganglia") to facilitate normal motor function. The basal ganglia is a group of structures deeper in the brain that work together to promote “wanted” movements and to prevent “unwanted” movements. The presence of dopamine is critical for the basal ganglia to function properly. Thus, it is the loss of dopamine that underlies many of the signs and symptoms experienced by PD patients and is the basis for many of the medications used to treat the symptoms of PD.

The current scientific evidence supports the notion that neurodegeneration associated with PD results from a complex interaction between genetic and environmental factors. Although about 20 percent of patients have another family member with PD, specific genetic causes of PD, with or without family history, are quite rare. Among the most common genes in which mutations increase the risk of PD include GBA1, LRRK2 and PRKN; other, much less frequent mutations in certain genes (e.g., SNCA, PARK7, VPS35, PINK1) also greatly increase the risk of PD. Unless the patients indicate strong interest in being tested for any of these gene mutations we do not routinely offer genetic testing, unless the patients are candidates for disease-modifying clinical trials targeting the various specific gene mutations (“precision medicine”). Although the vast majority of patients with PD have no identifiable gene mutation, this frequency markedly increases in young-onset and juvenile PD. Many epidemiological studies have suggested that certain environmental toxins, such as pesticides, and repeat head injuries may increase the risk of PD while others, such as smoking and caffeine, have been associated with lower risk of PD. No specific dietary, occupational, or other environmental causative factors, however, can be identified as risk factors in most cases.

Treatment

The treatment of PD has improved dramatically since the introduction of anticholinergic drugs such as trihexyphenidyl (Artane) and amantadine (Symmetrel) in the 1950s and, more importantly, levodopa in the 1960s. When combined with carbidopa (levodopa-carbidopa), levodopa has remained the most effective drug for the treatment of motor symptoms of PD.

Medications
Levodopa
Dopamine agonists
Monoamine oxidase type B inhibitors (MAO-I)
Catechol-o-methyl transferase (COMT) inhibitors
Anticholinergics
Medication Effects

When the dosage is optimized most patients can tolerate these medications well, but some side effects may occur such as nausea, lightheadedness, drowsiness, hallucinations, dyskinesias, ankle swelling, and other adverse effects. If any of these, or other, adverse events occur, the patients should notify their physicians. Usually, appropriate adjustments can be made to improve the tolerability of anti-PD medications. For example, initiating the medication at the lowest possible dose and increasing it slowly or taking it with meals improves tolerability.

Levodopa-carbidopa, the gold-standard treatment in PD, has to be initiated at low doses and gradually increased to obtain satisfactory relieve of motor symptoms. Almost all patients with PD respond well to levodopa but after few years many patients develop motor fluctuations (shortening of beneficial response to each dose of levodopa) and dyskinesias (abnormal involuntary movements, different from tremor). Patients who experience motor fluctuations should try to take their medications about 30 minutes before meals for maximal absorption and should avoid taking medications after eating protein-rich meals as the amino acids can interfere with the absorption of levodopa in the small intestine. Taking additional carbidopa (Lodosyn) or adding anti-nausea medications, such as ondansetron (Zofran) or hydroxyzine (Vistaril), or domperidone (Motilium) usually prevents or alleviates levodopa-related nausea. Hallucinations and other psychiatric complications of levodopa can be managed effectively with a class of medications known as the atypical neuroleptics, such as quetiapine (Seroquel) and clozapine (Clozaril), however, these medications have a risk of worsening PD symptoms. Pimavanserin (Nuplazid) is the first and only FDA approved medication shown to reduce hallucinations and psychosis in PD without affecting motor function. Drug-induced drowsiness can be effectively treated with caffeine, modafinil (Provigil) or armodafinil (Nuvigil); rarely CNS stimulants such as amphetamine-type drugs may be required.

Disease-modifying (neuroprotective) Therapy

Despite intensive search for neuroprotective therapies, thus far no medication, vitamin or any nutritional supplement has been shown to protect the dopamine-producing neurons. Some drugs, such as the MAOB-I and dopamine agonists, however, have been found to delay the need for levodopa, although there is controversy whether they favorably modify the disease through any neuroprotective effect. At our PDCMDC we are currently conducting a number of clinical trials, including strategies to reduce aggregated alpha-synuclein, that have the potential of finding disease-modifying strategies that will slow or prevent progression of PD.

In the age of digital technology and social media, patients may be subjected to medical news information and disinformation. There are often “new discoveries” and “miracle cures” within this medical news that can attract mainstream media and social attention. It is important for patients and physicians alike to maintain vigilance when interpreting these often exaggerated health claims and for patients to discuss questions and concerns with their physicians.

Procedures and Surgery

Patients with severe motor fluctuations and dyskinesias that cannot be adequately managed with medication adjustments may be candidates for levodopa infusions into small intestine (Duopa) or subcutaneously (Abbvie or Neuroderm) or deep brain stimulation.

Deep Brain Stimulation

Patients who continue to be troubled by their PD symptoms, particularly those who experience refractory tremor or levodopa-related complications (motor fluctuations and dyskinesias), may be considered candidates for surgery. Deep brain stimulation (DBS) has replaced the older, ablative, procedures, such as thalamotomy and pallidotomy, as the surgical treatment of choice in patients whose symptoms cannot be adequately controlled despite optimal medical therapy. See article on Deep Brain Stimulation for additional information about the role of surgery in the treatment of PD (www.jankovic.org).

MR-Guided Focused Ultrasound

Focused ultrasound (FUS) treatment may be an alternative to DBS for some patients with PD. Using advanced technology, neurosurgeons can treat deep in the brain with no external incisions. See article on MR-guided FUS for additional information about the role of this procedure in the treatment of PD (www.jankovic.org).

Physical Therapy and Exercise

Any discussion of management of PD would not be complete without emphasizing the importance of physical therapy and improved conditioning of patients with PD. Regular exercise program, combined with appropriate medical management, has been shown to delay the onset of physical disability associated with PD. Many studies have shown that exercise improves stamina and prevents fatigability, constipation, depression, sleep, osteoporosis, and memory loss.

Exercise also decreases the risk of stroke and heart attacks by reducing body weight, blood pressure, and risk of diabetes, and increasing the HDL ("good") cholesterol. For these and many other reasons ongoing vigorous exercise and physical fitness, which should include stretching, range of motion, and conditioning exercises should be highly encouraged, particularly if there are no physical contraindications.

Many patients wrongly assume that the "exercise" they get during their daily routines at work or at home, such as housecleaning, climbing stairs, and even mowing the lawn are sufficient forms of exercise. While these activities are encouraged, high-intensity regular exercise program, tailored to the needs of the individual patient, is critical for continued wellbeing. There are many studies that provide evidence that high-intensity exercise enhances dopaminergic transmission and favorably alters the course of the disease. The exercises should be designed to improve strength (e.g. using free weights, weight machines, and elastic bands) and overall fitness (e.g. walking, swimming). Water aerobics and dancing have been found particularly effective and safe.

Incorporation of external sensory cues in the rehabilitation protocol has been shown to extend short-term benefits of physical therapy. For example, a visual cue provided by an inverted L-shaped cane, horizontal beam on a walker, or by rhythmical sounds, such as listening to marching music, can significantly help overcome gait freezing.

Also, instructing the patient to take high steps or exaggerate their arm swing (e.g. simulating marching) may improve their gait and balance. Swimming or otherwise exercising in the water has the additional advantage in that there is very little stress on the joints and the resistance of the water improves muscle strength. This low impact activity also increases endurance and balance. Some patients prefer stretching and muscle relaxing exercises such as Pilates, tai chi, and yoga and they are clearly useful additions but should not replace the various conditioning exercises.

Recent animal research has provided strong evidence that exercise can increase resistance to brain insult or injury and can improve learning, mental, and motor performance. Patients should always check with their physicians before launching into a new exercise program. All precautions should be taken to prevent injuries.

Experimental Therapeutics

Our Center is engaged in clinical trials testing cutting-edge, innovative therapies designed to improve symptoms of PD or to favorably modify its progression. Please discuss your interest and willingness to participate in the therapeutic trials with one of our physicians or research coordinators. As new trials are being continuously approved, please consult ClinicalTrials.gov for the most up to date listing of available clinical trials for Parkinson’s disease. Please use the following link, which will automatically insert the "Parkinson's disease and Baylor" search terms for you. You can also search our clinical trials database.

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