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Understanding Dystonia

What are the Symptoms?

Dystonia causes involuntary repetitive twisting and sustained muscle contractions. These result in abnormal movements and postures. The symptoms usually begin in one body region, such as the neck, face, vocal cords, an arm or a leg, and then may spread to other parts of the body. When dystonia affects children, it often starts in a leg before spreading to other limbs and trunk. In adults, dystonia tends to remain localized to a body region and frequently affects first the upper body.

Dystonia usually occurs or worsens during voluntary movement. It may also happen with movement of other unaffected body regions or when the affected body part is at rest. Dystonia may lead to sustained fixed postures potentially causing permanent contractures. The symptoms of dystonia typically increase during stress, emotional upset or fatigue, and decrease during rest and sleep. Many people living with dystonia can temporarily suppress their symptoms by using “sensory tricks”. These are a unique feature of dystonia, consisting of touching the affected or an adjacent body part to decrease the pulling or posturing.

What Causes Dystonia?

Dystonia may be an inherited condition caused by genetic mutations. It can also result from exposure to certain drugs, birth injuries, strokes, or as a symptom of other neurological disorders. For many patients, however, the cause remains unknown. There are two main categories of causes of dystonia: primary and secondary (or non-primary).

Primary Dystonia

Primary dystonia is a condition in which dystonia is the only clinical feature. There is no evidence of cell death or a known cause. It is also known as idiopathic torsion dystonia. Primary dystonia is thought to have greater genetic contribution, even in the absence of a family history of dystonia. Several mutations have been identified in genes that are responsible for many cases of primary dystonia. The two most common and important genes associated with primary dystonia are DYT1 and DYT6. Most genetic forms of dystonia start with symptoms in childhood or adolescence. The DYT1 gene regulates the production of the torsinA protein. Mutations in this gene are associated with most cases of early-onset limb-onset primary dystonia and it is most common in individuals of North European Ashkenazi Jewish descent. The DYT6 gene was initially described in Mennonite families with generalized dystonia. This gene codes for the THAP1 protein. Mutations of this gene are associated with childhood and adult onset dystonia, usually affecting limbs and cervical and cranial muscles. Both DYT1 and DYT6 forms of dystonia tend to progress initially to involve multiple body regions. How mutations in these genes lead to dystonia is not yet well understood.  Commercial tests are available to determine if these genes are affected in individuals. However, for the majority of people living with primary dystonia, the cause remains unknown.

Secondary Dystonia

  • Myoclonus Dystonia, characterized by variable combinations of dystonia and myoclonus (marked, rapid, lightning-like muscle movements), with onset in childhood or adolescence. Myoclonus is often the most prominent feature, and tends to occur or worsen with voluntary movement. Its course is relatively benign with stabilization of symptoms after a few years. It is a hereditary condition and has been associated with mutations in the epsilon sarcoglycan gene (SCGE).
  • Dopa-responsive Dystonia (DRD) is a genetic disorder of childhood onset. It affects girls more commonly than boys. Children affected by DRD had onset of dystonia affecting usually the legs initially and many may have features of parkinsonism or exaggerated reflex responses. The symptoms generally become more severe as the day progresses and are worse at night. Their symptoms dramatically and characteristically improve with low-dose levodopa, and amino acid that is a precursor of the neurotransmitter dopamine. It has been associated with mutations in the guanosine triphosphate (GTP) cyclohydrolase I (GHC1 or DYT5) gene.
  • Rapid-onset Dystonia Parkinsonism (RDP) is a rare inherited disorder with onset in childhood or adulthood. It is characterized by sudden development over hours, days or weeks of a combination of dystonia and parkinsonism. The symptoms may in some cases develop after certain stressful events. Affected individuals may have abnormally low levels of homovanillic acid (HVA) in their spinal fluid. It has been linked to mutations in the ATP1A3 gene.
  • Wilson’s Disease is a rare genetic disorder of copper metabolism, in which copper accumulates first in the liver, and eventually in other organs, including the brain. Its neurological manifestations may include dystonia, parkinsonism and tremor.
  • Huntington’s Disease, also known as Huntington’s chorea is a hereditary progressive neurodegenerative disorder that results in behavioral and psychiatric abnormalities, cognitive decline and abnormal movements. While chorea is the most common involuntary movement in this condition (rapid irregular random jerky movements that may affect face, arm, legs or trunk), dystonia and parkinsonism may also be present.
  • Spinocerebellar Ataxias are a group of progressive degenerative inherited conditions characterized by slowly progressive incoordination of hands, speech, eye movements and gait (called ataxia, from Greek “not ordered”). Onset may be at any age. Other symptoms may include frequently dystonia. Frequently, atrophy of the cerebellum occurs.
  • Methymalonic Aciduria is an inherited disorder of metabolism. Neurological symptoms typically manifest during the first years of life and include generalize dystonia, difficulty swallowing and speaking and different degrees of paralysis.
  • Parkinson’s disease caused by Parkin mutations. Among the several genes that are known to cause PD (accounting nonetheless for a small minority of patients), one of the most important is a gene called Parkin. This gene creates a protein that helps break down proteins inside brain cells, and when mutated, this function is impaired, leading to neuronal death. PD patients with Parkin mutations present very similarly to sporadic or non-genetic PD, but those patients tend to have a younger onset of disease (less than 40) and to have prominent foot, hand and neck dystonia as symptoms.
  • Paroxysmal dystonia (also called paroxysmal dyskinesias) are neurological conditions characterized by discreet and sudden episodes of involuntary movements that may include dystonia or faster randomly irregular movements (chorea) and flailing movements of a limb (ballismus). The abnormal movements appear in a sudden and unpredictable manner with rapid return to normal function. They are classified based on precipitating factors into paroxysmal kinesigenic dyskinesia (PKD) and paroxysmal non-kinesigenic dyskinesia (PNKD). In PKD, the abnormal movements are provoked by sudden voluntary movement or startle. In PNKD, the attacks may occur spontaneously or be triggered by alcohol or caffeine. Genetic abnormalities have been recently linked to these conditions.

Age of onset

The age at onset is an important indicator of whether the dystonia is more likely to spread to other body regions. Early onset dystonia refers to dystonia that develops before age 21. The younger the patient at dystonia onset, the higher the likelihood that the dystonia may involve other areas. Late-onset dystonia begins after age 21. In patients with primary late-onset dystonia, the dystonia often begins in the upper body, such as the neck, head, neck, or an arm. Regions of the body Generalized Dystonia: is the most widespread form of dystonia; it affects the legs or one leg and the trunk, plus other regions, most commonly the arms. Focal Dystonia: involves only one region of the body, such as the neck, vocal cords or hand. Hemidystonia: affects one half of the body. Segmental Dystonia: affects two or more adjacent body regions, such as the neck and an arm. Multifocal Dystonia: affects two or more distant regions of the body, such as the upper face and the hand.

Where Can Focal Dystonia Occur?

Focal dystonia is a form of dystonia that is limited to one area of the body.

Commonly described forms of focal dystonia include:

Blepharospasm: is characterized by intermittent or sustained eyelid closure. It is caused by involuntary contractions of the muscles around the eyes. It leads to excessive blinking and spasms of eye closure.

Oromandibular Dystonia: or Meige’s syndrome, affects the lower facial and jaw muscles causing involuntary opening, closing or deviation of the jaw. The tongue may be also involved.

Cervical Dystonia: also called spasmodic torticollis or ST, affects the neck muscles leading to abnormal movements of the neck and head. It is the most common form of focal dystonia.

Laryngeal Dystonia: or spasmodic dysphonia affects the vocal cords. There are two forms of laryngeal dystonia. Adductor dysphonia, which is the most common form, causes the voice to have a restricted, strangled or hoarse quality. Abductor dysphonia leads to a breathy, whispering voice.

Limb Dystonia: affects the legs, feet, arms or hands. Upper limb dystonia often appears only when performing a specific task, such as writing (Writer’s Cramp). Other task-specific or occupational dystonias include musician’s dystonia and “the yips” that affect golfers. Highly repetitive and extreme motor precision in music performance are tasks capable of inducing focal action limb dystonia. Muscian’s dystonia can occur in professional musicians using almost any kind of instrument but are more common in piano players.

How is Dystonia Diagnosed?

Dystonia is usually diagnosed by a movement disorder neurologist. Proper diagnosis will be contingent on results from a thorough patient history, a careful family history, and complete physical and neurological examinations. Laboratory tests, imaging studies, and even genetic testing may be necessary to reach a diagnosis. Unfortunately, it is common for dystonia to be misdiagnosed or to remain undiagnosed when symptoms are mild. Many physicians are still unfamiliar with the disease. More education is needed to better inform the medical community about the symptoms associated with dystonia, and how to provide proper treatment.

How is Dystonia Treated?

The treatment depends on the cause of the dystonia. Treating the underlying condition in cases of secondary dystonia may improve the symptoms. There are three approaches to the treatment of dystonia, depending on the region of the body affected and the severity of the symptoms: medications, botulinum toxin injections and surgery. Physical therapy may be helpful as a supplement to other therapies.

Botulinum toxin injections:

Botulinum toxin injections are the treatments of choice for most forms of focal dystonia. The toxin is produced by the bacterium that causes botulism. When a small amount of commercially prepared toxin is selectively injected in the overactive muscles, it causes a change in the muscle firing, calming the abnormal movements for up to several months at a time.

Medications:

Segmental, multifocal and generalized dystonia are usually treated with oral medications. These include anticholinergic drugs (trihexyphenidyl or Artane®, benztropine or Cogentin®) and muscle relaxants or antispastic agents (diazepam or Valium®, clonazepam or Klonopin®, baclofen or Lioresal®). In addition, specific forms of dystonia can respond to particular medications. For example, dopa-responsive-dystonia is treated with levodopa (Sinemet®).

Surgery

Patients with widespread or severe debilitating dystonia can benefit from surgery if they are unresponsive to other treatments. The most widely used current surgical approach is called deep brain stimulation, or DBS. In this surgery, thin electrodes are implanted into a part of the basal ganglia called the globus pallidus and are attached to a pacemaker-like device implanted in the chest wall. These electrodes deliver controlled electrical pulses that can have a marked improvement of dystonia symptoms, especially for patients with generalized primary dystonia.

Complimentary Therapies:

Adjuvant therapy is an important component in the treatment of dystonia. Regular daily stretching exercises are a vital component to maintaining mobility, range of motion and flexibility. Physical therapy plays an important role in patients with cervical dystonia, usually as a supplement to other therapies such as botulinum toxin injections. Braces and other orthotics may be helpful for some patients by taking advantage of “sensory tricks” that involve touching a particular part of the body to relieve symptoms.  Biofeedback techniques have been studied as adjuvant therapies in dystonia, although long-term benefits have not been shown. Many patients report beneficial effects and symptom relief from other complimentary therapies such as yoga, tai chi and meditation techniques, although rigorous studies evaluating their efficacy are lacking.

Is There a Cure?

Although remarkable progress has been made in the study of dystonia in the last few years, there is not a known cure for it yet. Dystonia affects more people than Muscular Dystrophy, Huntington’s disease or Lou Gehrig’s disease combined, yet awareness of dystonia is limited. More research, treatments and education about its diagnosis are needed before a cure can be found.

How is Dystonia Related to Parkinson's?

Dystonia and Parkinson’s Disease (PD) are movement disorders that are closely related. First, both conditions can occur together in certain diseases. People living with PD may experience dystonia as an early symptom or as a complication of treatment. Dopa-responsive dystonia and rapid-onset-dystonia-parkinsonism are hereditary forms of dystonia in which PD is often also present. Other neurodegenerative disorders, such as Wilson’s disease, may have both dystonia and PD, in conjunction to other clinical features. Second, dystonia and PD share common treatments. Anticholinergic medications and levodopa may ameliorate both conditions, and DBS is a surgical alternative for both, although the final brain target may vary. Lastly, PD and dystonia are thought to result from dysfunction of the basal ganglia and their output, although the ultimate cause of the disorders is not known. Further research is necessary to determine the various underlying genetic, environmental, or other underlying mechanisms that may play a role in causing these two related disorders.

Understanding Parkinson’s Disease

What Causes Parkinson's Disease?

PD is a neurodegenerative disease. It occurs when certain nerve cells, or neurons, die or become impaired. This degeneration takes place in an area of the brain called the substantia nigra, located in the brainstem, which is one of the centers that control movement (also called the basal ganglia). Normally, these neurons produce a chemical known as dopamine, which is responsible for transmitting signals across the nerve pathways to produce smooth, purposeful movements. Loss of dopamine causes nerve cells to fire abnormally. This leaves people living with PD with difficulty directing or controlling their movements in a natural manner. People living with PD have usually lost 80% or more of dopamine-producing cells in the substantia nigra by the time symptoms are visually apparent. In addition, there is also neuronal cell loss and related pathology in other brain regions, responsible for other non-motor symptoms.

The main reason why these cells die or become impaired is still a mystery. Most scientists believe that both genetic and environmental factors are contributing causes. However, how they lead to PD is still unclear.

Genetics Factors of Parkinson’s Disease

While Parkinson’s disease is not usually inherited, familial forms exist and first-degree relatives of people living with PD are at slightly higher risk for the condition. When a genetic vulnerability is combined with exposure to some –yet unknown- environmental trigger, the changes for developing the disease increase. This genetic contribution appears to be stronger for those cases of early-onset PD.

The study of families in which PD appears to be inherited has resulted in the discovery of several genes associated with PD. There are two types of genes associated with disease. There are “causal genes” in which the causal gene alone, without the influence of other genes of environmental factors, guarantees that a person who inherits will very likely develop PD. This type of genetic PD is very rare. The second type, “associated genes”, do not cause PD on their own, but increase the risk of developing it. These genes usually need to be combined with other genes and environmental factors to cause PD.

At the present time, mutations in at least five genes have been firmly associated with PD: alpha-synuclein (SNCA or PARK1), parkin (PRKN or PARK2), DJ-1 (or PARK7), PTEN-induced putative kinase 1 (PINK1 or PARK6) and leucine-rich repeat kinase 2 (LRRK2 or PARK8). The identification of genes associated with PD has allowed scientists to better understand the disease. At the present time, genetic PD is treated in the same way as non-genetic or sporadic PD and clinical genetic testing is not usually performed. Because of the complexity associated with the genes associated with PD, genetic counseling is always recommended when performing genetic testing.

What are the Symptoms?

The cardinal motor symptoms of Parkinson’s Disease are listed below:

  • Slowness of movement (also known as Bradykinesia): This is typically an early sign and affects almost all people living with PD. It can be disabling because it interferes with normal daily activities. Bradykinesia includes difficulties with voluntary movement planning and execution. It is established by a decrease in speed, amplitude, dexterity and fluidity of movements. This includes decreased arm swing, changes in hand writing or micrographia, and shuffling gait. Other symptoms may include loss of facial expression, soft speech and difficulty swallowing.
  • Tremor: The tremor or involuntary shaking in PD can be seen in the hands, arms, legs, jaw or face. Typically, it starts on one side of the body, and it is visible when the affected body part is at rest or not in motion. Tremors that are present only with movement of the limb are usually due to other conditions. While it is present in many patients, approximately 25% of people living with PD never develop a tremor.
  • Rigidity: Rigidity or muscle stiffness may impair the full range of limb motion and interfere with normal activities. It may cause pain and a stooped posture.
  • Postural instability: The loss of balance reflexes known as postural instability usually begins later in the course of the disease. It can lead to falls and contributes greatly to the disability associated with PD.

PD can also cause a variety of other symptoms outside the realm of the motor system, known collectively as non-motor symptoms. The non-motor symptoms include diminished sense of smell, memory loss, sleep disturbances, depression, constipation, urinary frequency/urgency and erectile dysfunction among others.

How is Parkinson's Disease Diagnosed?

Currently, there is no specific test or marker for PD. Diagnosis is made by a neurologist following an examination. An MRI of the brain may be ordered to exclude other brain diseases. However, there are no clear changes on the MRI that can conclusively tell that a person has PD.

While not everyone will develop all four cardinal symptoms, at least two are required for diagnosis, in the absence of an alternative cause (for example, exposure to certain medications or history of strokes). When symptoms first appear and signs are subtle, a precise diagnosis may be difficult.

How is Parkinson's Treated?

The treatment of PD may be challenging, but unlike other neurodegenerative diseases, there is effective symptomatic treatment. The treatment should be orchestrated by a neurologist with movement disorders training and tailored to the individual patient. While medical and surgical therapy can provide long-lasting benefits, the ultimate goal of therapeutics in PD is neuroprotection (the development of drugs that can halt or slow down the progression). To date, no medication has demonstrated definite neuroprotection. However, monoamino oxidase inhibitors (MAOB-I) like rasagiline (Azilect®) may have disease modifying effects. There are also several other agents that have shown sufficient promise to warrant larger trials (creatine). In addition, DaTSCAN was approved by the FDA and it can be used as a tool to monitor the dopamine system in Parkinson’s disease.

There are a large number of drugs available to treat motor and non-motor aspects of PD. Symptoms can be controlled in numerous patients for many years.

Adjuvant therapy is paramount in PD. Regular daily exercise is a vital component to maintaining mobility, flexibility and balance. Research studies have shown that certain PD symptoms can be improved by aerobic exercises such as walking on a treadmill, dancing or biking, and by specific exercise modalities such as yoga, tai-chi or qi-gong. Improvement of mobility through exercise and physical therapy improves quality of life in PD. More so, studies in animal models of PD have shown that exercise may be neuroprotective, slowing the progression of disease, although more research is needed in this area.

For most people living with PD, maintaining a healthy lifestyle, proper diet and regular daily exercise are recommended for an improved quality of life. Support groups for both patients and carepartners are beneficial for psychological support, educational information and practical advice.

Drugs Used to Treat Parkinson’s Disease

  • Levodopa: also called L-dopa, is currently the single most effective drug for the treatment of PD. It is converted into dopamine in the brain, the neurotransmitter produced by cells in the substantia nigra. Levodopa helps control the main motor symptoms of PD. It is generally taken with another drug, carbidopa, to avoid its most common side effect, nausea. In the United States, this combination is commercialized under the name carbidopa-levodopa, Sinemet®, Sinemet® CR, or StaLevo®, a single pill containing carbidopa, levodopa and entacapone. There is controversy about how early in the disease levodopa therapy should be initiated.
  • Dopamine agonists: are drugs that stimulate dopamine receptors directly in the brain, mimicking the effect of levodopa. These medications are used to treat the motor symptoms of PD, particularly early in the disease and in younger patients. They are not as potent as levodopa, but they delay the onset of motor complications associated with chronic levodopa use. Agonists currently available in the United States are pramipexole (Mirapex®), ropinirole (Requip®), and apomorphine (Apokyn®). The rotigotine patch (Neupro®) was withdrawn from the U.S. market in April 2008, but it is still available in other countries.
  • COMT inhibitors: prevent the breakdown of dopamine in the brain. When taken with levodopa, the effect of a single dose is prolonged. The two COMT inhibitors available in United States are entacapone (Comtan®) and tolcapone (Tasmar®). A combination of levodopa, carbidopa and entacapone in a single tablet is available as StaLevo®.
  • Monoaminooxidase inhibitors (MAOB-I): Selegiline (Eldepryl®, Zelapar®) and rasagiline (Azilect®), the two MAOB-I commercially available for the treatment of PD, also inhibit the breakdown of dopamine in the brain, prolonging its effect. Recent trials suggest that rasagiline may have disease-modifying effects (neuroprotection). An older study on selegiline indicated that the medication also slowed down the disease. The results were however inconclusive, as the benefit could have also been explained by its symptomatic effects.
  • Anticholinergic medications: are drugs that block the effect of the chemical acetylcholine in the brain. Acetylcholine opposes the effect of dopamine. They are useful against tremor and stiffness. Their use is limited by their high rate of side effects. The most commonly used anticholinergic medications are trihexyphenidyl (Artane®) and benztropine (Cogentin®). Ethopropazine (Parsitan®) is available in Canada.
  • Amantadine: also known as Symmetrel® can relieve the motor symptoms of PD, particularly tremor. It has a more significant effect in reducing the abnormal movements (dyskinesias) caused by chronic dopaminergic treatment.
  • Other agents: medications to treat depression and anxiety, constipation, urinary and erectile dysfunction, and sleep disturbances may be necessary to optimize quality of life for people living with PD.

 

Complications of Drug Treatment

Most people living with PD have many years of uncomplicated treatment after the diagnosis. However, as the disease progresses over time, a significant proportion can develop treatment complications. Medication adjustments may be required to minimize them.

Motor Complications of Treatment

Motor fluctuations: refers to as “wearing-off”, “on-off” and “dose failure”. “Wearing-off” is the shortening of the benefit period of a single medication dose. An “on-off” period is a sudden and unpredictable loss of the effect of a drug and “dose failure” is the lack of any benefit from one particular medication dose.

  • Dyskinesias: are uncontrollable, abnormal dance-like movements that may occur in people living with PD after years of treatment with Levodopa. These movements usually occur at the peak effect of a dose of Levodopa. Amantadine may ameliorate this complication, as well as deep brain stimulation.
  • “Off” Dystonia: is manifested by abnormal twisting movements, particularly of the fingers and toes. It typically occurs in the mornings before the first dose of medication.
  • Freezing: occurs when there is a sudden inability or hesitation to move (motor block). It may appear at the beginning of a movement, when going through doorways or narrow passages or when turning. It may lead to falls. Freezing does not always respond to medications.

Non-Motor Complications of Treatment

  • Psychosis: may result from side effects of antiparkinsonian medications. It includes hallucinations, delusions and disorientation. It may also be a feature of disease progression. Reducing and eliminating some medications can be helpful. The use of atypical antipsychotic medications, such as quetiapine (Seroquel®) or clozapine (Clozaril®), may be necessary in some cases.
  • Orthostatic hypotension: occurs when there is a drop in blood pressure upon standing. It may cause dizziness, lightheadedness and even fainting in some cases.

Brain Surgery

When symptoms are inadequately treated with medications, brain surgery is an option. Not every person living with PD is a good candidate for surgery. An ideal candidate is an otherwise healthy person with PD who responds well to the medication but has developed severe motor complications.

There are two surgical procedures for PD: lesioning and deep brain stimulation (DBS). Lesion procedures (also known as pallidotomy or thalamotomy) deliver energy to heat and destroy a small part of the brain. These procedures are gradually being replaced by DBS, as the latter is a reversible and programmable therapy. DBS therapy uses a medical device, similar to a pacemaker, implanted in the chest wall, and a thin, flexible wire, called a lead. The lead is located deep in the brain, in three possible areas that control movement. The device sends mild electrical signals to the lead that block some of the brain messages that cause the motor symptoms. When used in an adequate candidate, DBS can lead to improvement of all motor features of PD, and many patients are able to decrease their medications. Risks of DBS include surgical risks (hemorrhage or infection) as well as hardware complications (leads breaking, electrode malfunction or battery failure). Side effects may include language impairment and walking difficulties.

Is There a Cure?

Remarkable progress has occurred in the study of PD in the last few years. To date, however, there is no known cure for the disease. For most people living with PD, symptoms can be controlled for many years, and life expectancy is not significantly reduced.

How is Parkinson's Disease Related to Dystonia?

Dystonia and Parkinson’s Disease (PD) are movement disorders that are closely related. First, both conditions can occur together in certain diseases. People living with PD may experience dystonia as an early symptom or as a motor complication of treatment. Dopa-Responsive Dystonia and Rapid-Onset-Dystonia-Parkinsonism are hereditary forms of dystonia in which PD is often also present. Other neurodegenerative disorders, such as Wilson’s disease, may have both dystonia and PD, in conjunction to other clinical features. Second, dystonia and PD share common treatments. Anticholinergic medications and levodopa may ameliorate both conditions, and DBS is a surgical alternative for both, although the final brain target may vary. Lastly, PD and dystonia are thought to result from dysfunction of the basal ganglia and their output, although the ultimate cause of the disorders is not known. Further research is necessary to determine the various underlying genetic, environmental, or other underlying mechanisms that may play a role in causing these two related disorders.

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