A tremor is an involuntary,somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements (oscillations or twitching) of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal cords, trunk, and legs. Most tremors occur in the hands. In some people, tremor is a symptom of another neurological disorder. A very common kind of tremor is the chattering of teeth, usually induced by cold temperatures or by fear.

Causes

Tremor can be a symptom associated with disorders in those parts of the brain that control muscles throughout the body or in particular areas, such as the hands. Neurological disorders or conditions that can produce tremor include multiple sclerosis, stroke, traumatic brain injury, chronic kidney disease and a number of neurodegenerative diseases that damage or destroy parts of the brainstem or the cerebellum, Parkinson's disease being the one most often associated with tremor. Other causes include the use of drugs (such as amphetamines, caffeine, corticosteroids, SSRI), alcohol abuse or withdrawal, mercury poisoning; this is also in infants with phenylketonuria (PKU), overactive thyroid or liver failure. Tremors can be an indication of hypoglycemia, along with palpitations, sweating and anxiety. Tremor can also be caused from lack of sleep, lack of vitamins, or increased stress.[citation needed] Deficiencies of magnesium and thiamine have also been known to cause tremor or shaking, which resolves when the deficiency is corrected. See magnesium in biology. Some forms of tremor are inherited and run in families, while others have no known cause. Tremors can also be caused by some spider bites, e.g. the redback spider of Australia.

Characteristics may include a rhythmic shaking in the hands, arms, head, legs, or trunk; shaky voice; difficulty writing or drawing; or problems holding and controlling utensils, such as a fork. Some tremors may be triggered by or become exaggerated during times of stress or strong emotion, when the individual is physically exhausted, or during certain postures or movements.

Tremor may occur at any age but is most common in middle-age and older persons. It may be occasional, temporary, or occur intermittently. Tremor affects men and women equally.

[edit] Etiologies

Tremor is most commonly classified by clinical features and cause or origin. Some of the better known forms of tremor, with their symptoms, include the following:

Cerebellar tremor (also known as intention tremor) is a slow, broad tremor of the extremities that occurs at the end of a purposeful movement, such as trying to press a button or touching a finger to the tip of one’s nose. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from stroke, tumor, or

disease such as multiple sclerosis or some inherited degenerative disorder. It can also result from chronic alcoholism or overuse of some medicines. In classic cerebellar tremor, a lesion on one side of the brain produces a tremor in that same side of the body that worsens with directed movement. Cerebellar damage can also produce a “wing-beating” type of tremor called rubral or Holmes’ tremor — a combination of rest, action, and postural tremors. The tremor is often most prominent when the affected person is active or is maintaining a particular posture. Cerebellar tremor may be accompanied by other manifestations of ataxia, including dysarthria (speech problems), nystagmus (rapid, involuntary rolling of the eyes), gait problems and postural tremor of the trunk and neck. Titubation is tremor of the head and is of cerebellar origin.

Dystonic tremor occurs in individuals of all ages who are affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body and is seen most often when the patient is in a certain position or moves a certain way. The pattern of dystonic tremor may differ from essential tremor. Dystonic tremors occur irregularly and often can be relieved by complete rest. Touching the affected body part or muscle may reduce tremor severity (a geste antagoniste). The tremor may be the initial sign of dystonia localized to a particular part of the body.

Essential tremor (sometimes called benign essential tremor) is the most common of the more than 20 types of tremor. Although the tremor may be mild and nonprogressive in some people, in others, the tremor is slowly progressive, starting on one side of the body but affecting both sides within 3 years. The hands are most often affected but the head, voice, tongue, legs, and trunk may also be involved. Head tremor may be seen as a “yes-yes” or “no-no” motion. Essential tremor may be accompanied by mild gait disturbance. Tremor frequency may decrease as the person ages, but the severity may increase, affecting the person’s ability to perform certain tasks or activities of daily living. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Onset is most common after age 40, although symptoms can appear at any age. It may occur in more than one family member. Children of a parent who has essential tremor have a 50 percent chance of inheriting the condition. Essential tremor is not associated with any known pathology.

Orthostatic tremor is characterized by fast (>12Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. No other clinical signs or symptoms are present and the shaking ceases when the patient sits or is lifted off the ground. The high frequency of the tremor often makes the tremor look like rippling of leg muscles while standing. Orthostatic tremor may also occur in patients who have essential tremor.

Parkinsonian tremor is caused by damage to structures within the brain that control movement. This resting tremor, which can occur as an isolated symptom or be seen in other disorders, is often a precursor to Parkinson's disease (more than 25 percent of patients with Parkinson’s disease have an associated action tremor). The tremor, which is classically seen as a "pill-rolling" action of the hands that may also affect the chin, lips, legs, and trunk, can be markedly increased by stress or emotions. Onset of parkinsonian tremor is generally after age 60. Movement starts in one limb or on one side of the body and usually progresses to include the other side.

Physiologic tremor occurs in every normal individual and has no clinical significance. It is rarely visible to the eye and may be heightened by strong emotion (such as anxiety or fear), physical exhaustion, hypoglycemia, hyperthyroidism, heavy metal poisoning, stimulants, alcohol withdrawal or fever. It can be seen in all voluntary muscle groups and can be detected by extending the arms and placing a piece of paper on top of the hands. Enhanced physiologic tremor is a strengthening of physiologic tremor to more visible levels. It is generally not caused by a neurological disease but by reaction to certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. It is usually reversible once the cause is corrected.

Psychogenic tremor (also called hysterical tremor) can occur at rest or during postural or kinetic movement. The characteristics of this kind of tremor may vary but generally include sudden onset and remission, increased incidence with stress, change in tremor direction and/or body part affected, and greatly decreased or disappearing tremor activity when the patient is distracted. Many patients with psychogenic tremor have a conversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which is present at rest, at posture and with intention. This tremor is associated with conditions which affect the red nucleus in the midbrain, classically unusual strokes.

Tremor can result from other conditions as well.

Alcoholism , excessive alcohol consumption, or alcohol withdrawal can kill certain nerve cells, resulting a tremor known as asterixis. Conversely, small amounts of alcohol may help to decrease familial and essential tremor, but the mechanism behind this is unknown.

Tremor in peripheral neuropathy may occur when the nerves that supply the body’s muscles are traumatized by injury, disease, abnormality in the central nervous system, or as the result of systemic illnesses. Peripheral neuropathy can affect the whole body or certain areas, such as the hands, and may be progressive. Resulting sensory loss may be seen as a tremor or ataxia (inability to coordinate voluntary muscle movement) of the affected limbs and problems with gait and balance. Clinical characteristics may be similar to those seen in patients with essential tremor.

Tobacco withdrawal symptoms also include tremor.

[edit] Diagnosis

During a physical exam a doctor can determine whether the tremor occurs primarily during action or at rest. The doctor will also check for tremor symmetry, any sensory loss, weakness or muscle atrophy, or decreased reflexes. A detailed family history may indicate if the tremor is inherited. Blood or urine tests can detect thyroid malfunction, other metabolic causes, and abnormal levels of certain chemicals that can cause tremor. These tests may also help to identify contributing causes, such as drug interaction, chronic alcoholism, or another condition or disease. Diagnostic imaging using CT or MRI imaging may help determine if the tremor is the result of a structural defect or degeneration of the brain.

The doctor will perform a neurological examination to assess nerve function and motor and sensory skills. The tests are designed to determine any functional limitations, such as difficulty with handwriting or the ability to hold a utensil or cup. The patient may be asked to place a finger on the tip of her or his nose, draw a spiral, or perform other tasks or exercises.

The doctor may order an electromyogram to diagnose muscle or nerve problems. This test measures involuntary muscle activity and muscle response to nerve stimulation.

[edit] Categories

The degree of tremor should be assessed in four positions. The tremor can then be classified by which position most accentuates the tremor:[2]

Position Name Description

At restResting tremors

Tremors that are worse at rest include Parkinsonian syndromes and essential tremor if severe. This includes drug-induced tremors from blockers of dopamine receptors such as haloperidol and other antipsychotic drugs.

During contraction (e.g. a tight fist while the arm is resting and supported)

Contraction tremors

Tremors that are worse during supported contraction include essential tremor and also cerebellar and exaggerated physiologic tremors such as a hyperadrenergic state or hyperthyroidism[2]. Drugs such as adrenergics, anticholinergics, and xanthines can exaggerate physiologic tremor.

During posture (e.g. with the arms elevated against gravity such as in a 'bird-wing' position)

Posture tremors

Tremors that are worse with posture against gravity include essential tremor and exaggerated physiologic tremors[2].

During intention (e.g. finger to nose test)

Intention tremors

Intention tremors are tremors that are worse during intention, e.g. as the patient's finger approaches a target, including cerebellar disorders.

[edit] Treatment

There is no cure for most tremors. The appropriate treatment depends on accurate diagnosis of the cause. Some tremors respond to treatment of the underlying condition. For example, in some cases of psychogenic tremor, treating the patient’s underlying psychological problem may cause the tremor to disappear.

[edit] Medications

Symptomatic drug therapy is available for several forms of tremor:

Parkinsonian tremor drug treatment involves L-DOPA and/or dopamine-like drugs such as pergolide, bromocriptine and ropinirole. Other drugs used to lessen parkinsonian tremor include amantadine and anticholinergics.

Essential tremor may be treated with beta blockers (such as propranolol and nadolol) or primidone, an anticonvulsant.

Cerebellar tremor typically does not respond to medical treatment.

Rubral tremor patients may receive some relief using L-DOPA or anticholinergic drugs.

Dystonic tremor may respond to diazepam, anticholinergic drugs, and intramuscular injections of botulinum toxin. Botulinum toxin is also prescribed to treat voice and head tremors and several movement disorders.

Primary orthostatic tremor sometimes is treated with a combination of diazepam and primidone.

Enhanced physiologic tremor is usually reversible once the cause is corrected. If symptomatic treatment is needed, beta blockers can be used.

[edit] Lifestyle

Eliminating tremor “triggers” such as caffeine and other stimulants from the diet is often recommended.

Physical therapy may help to reduce tremor and improve coordination and muscle control for some patients. A physical therapist will evaluate the patient for tremor positioning, muscle control, muscle strength, and functional skills. Teaching the patient to brace the

affected limb during the tremor or to hold an affected arm close to the body is sometimes useful in gaining motion control. Coordination and balancing exercises may help some patients. Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.

[edit] Surgery

Surgical intervention such as thalamotomy and deep brain stimulation may ease certain tremors. These surgeries are usually performed only when the tremor is severe and does not respond to drugs.

Thalamotomy, involving the creation of lesions in the brain region called the thalamus, is quite effective in treating patients with essential, cerebellar, or parkinsonian tremor. This in-hospital procedure is performed under local anesthesia, with the patient awake. After the patient’s head is secured in a metal frame, the surgeon maps the patient’s brain to locate the thalamus. A small hole is drilled through the skull and a temperature-controlled electrode is inserted into the thalamus. A low-frequency current is passed through the electrode to activate the tremor and to confirm proper placement. Once the site has been confirmed, the electrode is heated to create a temporary lesion. Testing is done to examine speech, language, coordination, and tremor activation, if any. If no problems occur, the probe is again heated to create a 3-mm permanent lesion. The probe, when cooled to body temperature, is withdrawn and the skull hole is covered. The lesion causes the tremor to permanently disappear without disrupting sensory or motor control.

Deep brain stimulation (DBS) uses implantable electrodes to send high-frequency electrical signals to the thalamus. The electrodes are implanted as described above. The patient uses a hand-held magnet to turn on and turn off a pulse generator that is surgically implanted under the skin. The electrical stimulation temporarily disables the tremor and can be “reversed,” if necessary, by turning off the implanted electrode. Batteries in the generator last about 5 years and can be replaced surgically. DBS is currently used to treat parkinsonian tremor and essential tremor.

The most common side effects of tremor surgery include dysarthria (problems with motor control of speech), temporary or permanent cognitive impairment (including visual and learning difficulties), and problems with balance.

[edit] Biomechanical loading

As well as medication, rehabilitation programmes and surgical interventions, the application of biomechanical loading on tremor movement has been shown to be a technique that is able to suppress the effects of tremor on the human body. It has been established in the literature that most of the different types of tremor respond to biomechanical loading. In particular, it has been clinically tested that the increase of damping and/or inertia in the upper limb leads to a reduction of the tremorous motion. Biomechanical loading relies on an external device that either passively or actively acts

mechanically in parallel to the upper limb to counteract tremor movement. This phenomenon gives rise to the possibility of an orthotic management of tremor.

Starting from this principle, the development of upper-limb non-invasive ambulatory robotic exoskeletons is presented as a promising solution for patients who cannot benefit from medication to suppress the tremor. In this area robotic exoskeletons have emerged, in the form of orthoses, to provide motor assistance and functional compensation to disabled people. An orthosis is a wearable device that acts in parallel to the affected limb. In the case of tremor management, the orthosis must apply a damping or inertial load to a selected set of limb articulations.

Recently, some studies demonstrated that exoskeletons could achieve a consistent 40% of tremor power reduction for all users, being able to attain a reduction ratio in the order of 80% tremor power in specific joints of users with severe tremor.[3] In addition, the users reported that the exoskeleton did not affect their voluntary motion. These results indicate the feasibility of tremor suppression through biomechanical loading.

The main drawbacks of this mechanical management of tremor are (1) the resulting bulky solutions, (2) the inefficiency in transmitting loads from the exoskeleton to the human musculo-skeletal system and (3) technological limitations in terms of actuator technologies. In this regard, current trends in this field are focused on the evaluation of the concept of biomechanical loading of tremor through selective Functional Electrical Stimulation (FES) based on a (Brain-to-Computer Interaction) BCI-driven detection of involuntary (tremor) motor activity.[4]

Dystonia is a movement disorder which causes involuntary contractions of your muscles. These contractions result in twisting and repetitive movements. Sometimes they are painful.

Dystonia can affect just one muscle, a group of muscles or all of your muscles. Symptoms can include tremors, voice problems or a dragging foot. Symptoms often start in childhood. They can also start in the late teens or early adulthood. Some cases worsen over time. Others are mild.

Some people inherit dystonia. Others have it because of another disease. Either way, researchers think that a problem in the part of the brain that handles messages about muscle contractions might cause dystonia. There is no cure. Instead, doctors use medicines, surgery, physical therapy and other treatments to reduce or eliminate muscle spasms and pain.

What are the dystonias?

The dystonias are movement disorders in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The movements, which are involuntary and sometimes painful, may affect a single muscle; a group of muscles such as those in the arms, legs, or neck; or the entire body. Those with dystonia usually have normal intelligence and no associated psychiatric disorders.

What are the symptoms?

Dystonia can affect many different parts of the body. Early symptoms may include a deterioration in handwriting after writing several lines, foot cramps, and/or a tendency of one foot to pull up or drag; this may occur "out of the blue" or may occur after running or walking some distance. The neck may turn or pull involuntarily, especially when the patient is tired or stressed. Sometimes both eyes will blink rapidly and uncontrollably, rendering a person functionally blind. Other possible symptoms are tremor and voice or speech difficulties. The initial symptoms can be very mild and may be noticeable only after prolonged exertion, stress, or fatigue. Over a period of time, the symptoms may become more noticeable and widespread and be unrelenting; sometimes, however, there is little or no progression. top

How are the dystonias classified?

One way to classify the dystonias is according to the parts of the body they affect:

Generalized dystonia affects most or all of the body. Focal dystonia is localized to a specific part of the body. Multifocal dystonia involves two or more unrelated body parts. Segmental dystonia affects two or more adjacent parts of the body. Hemidystonia involves the arm and leg on the same side of the body.

Some patterns of dystonia are defined as specific syndromes:

Torsion dystonia, previously called dystonia musculorum deformans or DMD, is a rare, generalized dystonia that may be inherited, usually begins in childhood, and becomes progressively worse. It can leave individuals seriously disabled and confined to a wheelchair. Genetic studies have revealed an underlying cause in many patients - a mutation in a gene named DYT1 (see "What research is being done?"). And it has been discovered that this gene is related not only to generalized dystonia, but also to some forms of focal dystonia. Note, however, that most dystonia, of any type, is not due to this gene and has an unknown cause.

Cervical dystonia, also called spasmodic torticollis, or torticollis, is the most common of the focal dystonias. In torticollis, the muscles in the neck that control the position of the head are affected, causing the head to twist and turn to one side. In addition, the head may be pulled forward or backward. Torticollis can occur at any age, although most individuals first experience symptoms in middle age. It often begins slowly and usually reaches a plateau. About 10 to 20 percent of those with torticollis experience a spontaneous remission, but unfortunately the remission may not be lasting.

Blepharospasm, the second most common focal dystonia, is the involuntary, forcible closure of the eyelids. The first symptoms may be uncontrollable blinking. Only one eye may be affected initially, but eventually both eyes are usually involved. The spasms may leave the eyelids completely closed causing functional blindness even though the eyes and vision are normal.

Cranial dystonia is a term used to describe dystonia that affects the muscles of the head, face, and neck. Oromandibular dystonia affects the muscles of the jaw, lips, and tongue. The jaw may be pulled either open or shut, and speech and swallowing can be difficult. Spasmodic dysphonia involves the muscles of the throat that control speech. Also called spastic dysphonia or laryngeal dystonia, it causes strained and difficult speaking or breathy and effortful speech. Meige's syndrome is the combination of blepharospasm and oromandibular dystonia and sometimes spasmodic dysphonia. Spasmodic torticollis can be classified as a type of cranial dystonia.

Writer's cramp is a dystonia that affects the muscles of the hand and sometimes the forearm, and only occurs during handwriting. Similar focal dystonias have also been called typist's cramp, pianist's cramp, and musician's cramp.

Dopa-responsive dystonia (DRD), of which Segawa's dystonia is an important variant, is a condition successfully treated with drugs. Typically, DRD begins in childhood or adolescence with progressive difficulty in walking and, in some cases, spasticity. In Segawa's dystonia, the symptoms fluctuate during the day from relative mobility in the morning to increasingly worse disability in the afternoon and evening as well as after exercise. The diagnosis of DRD may be missed since it mimics many of the symptoms of cerebral palsy.

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What do scientists know about the dystonias?

Investigators believe that the dystonias result from an abnormality in an area of the brain called the basal ganglia where some of the messages that initiate muscle contractions are processed. Scientists suspect a defect in the body's ability to process a group of chemicals

called neurotransmitters that help cells in the brain communicate with each other. Some of these neurotransmitters include:

GABA (gamma-aminobutyric acid), an inhibitory substance that helps the brain maintain muscle control.

Dopamine, an inhibitory chemical that influences the brain's control of movement.

Acetylcholine, an excitatory chemical that helps regulate dopamine in the brain. In the body, acetylcholine released at nerve endings causes muscle contraction.

Norepinephrine and serotonin, inhibitory chemicals that help the brain regulate acetylcholine.

Acquired dystonia, also called secondary dystonia, results from environmental or disease-related damage to the basal ganglia. Birth injury (particularly due to lack of oxygen), certain infections, reactions to certain drugs, heavy-metal or carbon monoxide poisoning, trauma, or stroke can cause dystonic symptoms. Dystonias can also be symptoms of other diseases, some of which may be hereditary.

About half the cases of dystonia have no connection to disease or injury and are called primary or idiopathic dystonia. Of the primary dystonias, many cases appear to be inherited in a dominant manner; i.e., only one carrier parent need contribute the dystonia gene for the disease to occur, each child having a 50/50 chance of being a carrier. In dystonia, however, a carrier may or may not develop a dystonia and the symptoms may vary widely even among members of the same family. The product of one defective gene appears to be sufficient to cause the chemical imbalances that may lead to dystonia; but the possibility exists that another gene or genes and environmental factors may play a role.

Some cases of primary dystonia may have different types of hereditary patterns. Knowing the pattern of inheritance can help families understand the risk of passing dystonia along to future generations.

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When do symptoms occur?

In some individuals, symptoms of a dystonia appear in childhood, approximately between the ages of 5 and 16, usually in the foot or in the hand. In generalized dystonia, the involuntary dystonic movements may progress quickly to involve all limbs and the torso, but the rate of progression usually slows noticeably after adolescence.

For other individuals, the symptoms emerge in late adolescence or early adulthood. In these cases, the dystonia often begins in upper body parts, with symptoms progressing

slowly. A dystonia that begins in adulthood is more likely to remain as a focal or segmental dystonia.

Dystonias often progress through various stages. Initially, dystonic movements are intermittent and appear only during voluntary movements or stress. Later, individuals may show dystonic postures and movements while walking and ultimately even while they are relaxed. Dystonic motions may lead to permanent physical deformities by causing tendons to shorten.

In secondary dystonias due to injury or stroke, people often have abnormal movements of just one side of the body, which may begin at the time of the brain injury or sometime afterward. Symptoms generally plateau and do not usually spread to other parts of the body.

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Are there any treatments?

No one treatment has been found universally effective. Instead, physicians use a variety of therapies aimed at reducing or eliminating muscle spasms and pain.

Medication. Several classes of drugs that may help correct imbalances in neurotransmitters have been found useful. But response to drugs varies among patients and even in the same person over time. The most effective therapy is often individualized, with physicians prescribing several types of drugs at different doses to treat symptoms and produce the fewest side effects. Note that not all of the medications mentioned below are currently available for patients in the United States.

Frequently, the first drug administered belongs to a group that reduces the level of the neurotransmitter acetylcholine. Drugs in this group include trihexyphenidyl, benztropine, and procyclidine HCl. Sometimes these medications can be sedating, especially at higher doses, and this can limit their usefulness.

Drugs that regulate the neurotransmitter GABA may be used in combination with these drugs or alone in patients with mild symptoms. GABA-regulating drugs include the muscle relaxants diazepam, lorazepam, clonazepam, and baclofen.

Other drugs act on dopamine, a neurotransmitter that helps the brain fine-tune muscle movement. Some drugs which increase dopamine effects include levodopa/carbidopa and bromocriptine. DRD has been remarkably responsive to small doses of this dopamine-boosting treatment. On the other hand, patients have occasionally benefited from drugs

that decrease dopamine, such as reserpine or the investigational drug tetrabenazine. Once again, side effects can restrict the use of these medications.

Anticonvulsants including carbamazepine, usually prescribed to control epilepsy, have occasionally helped individuals with dystonia.

Botulinum toxin. Minute amounts of this familiar toxin can be injected into affected muscles to provide temporary relief of focal dystonias. First used to treat blepharospasm, such injections have gained wider acceptance among physicians for treating other focal dystonias. The toxin stops muscle spasms by blocking release of the excitatory neurotransmitter acetylcholine. The effect lasts for up to several months before the injections have to be repeated.

Surgery and other treatments. Surgery may be recommended for some patients when medication is unsuccessful or the side effects are too severe. In selected cases, advanced generalized dystonias have been helped, at least temporarily, by surgical destruction of parts of the thalamus, a structure deep in the brain that helps control movement. Speech disturbance is a special risk accompanying this procedure, since the thalamus lies near brain structures that help control speech. Surgically cutting or removing the nerves to the affected muscles has helped some focal dystonias, including blepharospasm, spasmodic dysphonia and torticollis. The benefits of these operations, however, can be short-lived. They also carry the risk of disfigurement, can be unpredictable, and are irreversible.

Some patients with spasmodic dysphonia may benefit from treatment by a speech-language pathologist. Physical therapy, splinting, stress management, and biofeedback may also help individuals with certain forms of dystonia

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What research is being done?

The ultimate goals of research are to find the cause(s) of the dystonias so that they can be prevented, and to find ways to cure or more effectively treat people now affected. The National Institute of Neurological Disorders and Stroke (NINDS), a unit of the Federal Government's National Institutes of Health (NIH), is the agency with primary responsibility for brain and neuromuscular research. NINDS sponsors research on dystonia both in its facilities at the NIH and through grants to medical centers throughout the country. Scientists at the National Institute on Deafness and Other Communication Disorders (NIDCD), also part of the NIH, are studying improved treatments for speech and voice disorders associated with dystonias. The National Eye Institute (NEI) supports work on the study of blepharospasm and related problems (see above) and the National

Institute of Child Health and Human Development (NICHD) supports work on dystonia, including the rehabilitation aspects of the disorder.

Scientists at the NINDS laboratories have conducted detailed investigations of the pattern of muscle activity in persons with focal dystonias. One of the most important characteristics is the failure of reciprocal inhibition, a normal process in which muscles with opposite actions work without opposing each other. In dystonia, the tightening of muscles is associated with an abnormal pattern of muscles fighting each other. Other studies at the NINDS have probed the spinal reflex function and found abnormalities consistent with the defect in reciprocal inhibition. Other studies using EEG analysis and neuroimaging are probing brain activity and its relation to these observations.

The search for the gene or genes responsible for some forms of dominantly inherited dystonias continues. In 1989 a team of researchers mapped a gene for early-onset torsion dystonia to chromosome 9; the gene was subsequently named DYT1. In 1997 the team sequenced the DYT1 gene and found that it codes for a previously unknown protein now called "torsin A." The discovery of the DYT1 gene and the torsin A protein provides the opportunity for prenatal testing, allows doctors to make a specific diagnosis in some cases of dystonia, and permits the investigation of molecular and cellular mechanisms that lead to disease.

The gene for Segawa's dystonia has been found. It codes for an enzyme important in the brain's manufacture of dopamine.

Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless (hence the word's origin in Ancient Greek: from καθίζειν kathízein „to sit“ with a privative a as prefix expressing negation or absence; literally meaning inability to sit). It can be a side effect of medications, mainly neuroleptic antipsychotics especially the phenothiazines (such as perphenazine and chlorpromazine), thioxanthenes (such as flupenthixol and zuclopenthixol) and butyrophenones (such as haloperidol (Haldol)), piperazines (such as ziprasidone), antispasmodics (such as metoclopramide), and usually to a lesser extent antidepressants. Akathisia can also, to a lesser extent, be caused by Parkinson's disease and related syndromes.[1] Antipsychotic psychotropic drugs may cause Parkinsonian like symptoms due to blockage of dopamine receptors in the nigrostriatal pathway of the brain. Another major cause is the withdrawal from opioid medications.

Akathisia may range in intensity from a mild sense of disquiet or anxiety, to a total inability to sit still, accompanied by overwhelming anxiety, malaise, and severe dysphoria (manifesting as an almost indescribable sense of terror and doom). The condition is difficult for the patient to describe and is often misdiagnosed. When misdiagnosis occurs in antipsychotic neuroleptic-induced akathisia, more antipsychotic neuroleptics may be prescribed, potentially worsening the symptoms. [1] High-functioning

patients have described the feeling as a sense of inner tension and torment or chemical torture.

The presence and severity of akathisia can be measured using the Barnes Akathisia Scale

Description

Reports of akathisic states can be found in the medical literature before the advent of neuroleptics.[4] Healy, et al. (2006), described the following regarding akathisia: tension, insomnia, a sense of discomfort, motor restlessness, and marked anxiety and panic. Increased labile affect can result, such as weepiness. Interestingly, in some people the opposite response to SSRIs occurs, in the form of emotional blunting; but sufficient clinical research has not yet been made in this area.[5]

Jack Henry Abbot (1981) described the effects of akathisia produced by antipsychotic drugs:

These drugs, in this family, do not calm or sedate the nerves. They attack. They attack from so deep inside you, you cannot locate the source of the pain ... The muscles of your jawbone go berserk, so that you bite the inside of your mouth and your jaw locks and the pain throbs. For hours every day this will occur. Your spinal column stiffens so that you can hardly move your head or your neck and sometimes your back bends like a bow and you cannot stand up. The pain grinds into your fiber ... You ache with restlessness, so you feel you have to walk, to pace. And then as soon as you start pacing, the opposite occurs to you; you must sit and rest. Back and forth, up and down you go in pain you cannot locate, in such wretched anxiety you are overwhelmed, because you cannot get relief even in breathing.—Jack Henry Abbot, In the Belly of the Beast (1981/1991). Vintage Books, 35–36. Quoted in Robert Whitaker, Mad in America (2002, ISBN 0738207993), 187.

Patients who suffer from neuroleptic-induced akathisia often react by refusing treatment. At the extreme end, patients who have been treated with neuroleptic antipsychotics for psychotic episodes or prochlorperazine for nausea may rarely run away from hospitals or emergency rooms due to this disconcerting sensation.[6]

[edit] Causes

Akathisia is most often seen as a side effect of antipsychotic medications, but has other causes as well:

Antipsychotics[7] such as haloperidol (Haldol), droperidol, pimozide, trifluoperazine, amisulpride, risperidone, aripiprazole (Abilify) and asenapine (Saphris). Less common in sedating antipsychotics such as zuclopenthixol (Cisordinol) or chlorpromazine where anticholinergic and antihistaminergic effects counteract akathisia to a degree.

SSRIs , such as fluoxetine (Prozac).[8] It has also been documented with the use of paroxetine (Paxil).[5] Akathisia has been studied as the mechanism by which SSRI-induced suicidality occurs.[8]

Other antidepressants, such as venlafaxine, the tricyclics and trazodone (Desyrel). Certain anti-emetic drugs, particularly the dopamine blockers, such as

metoclopramide (Reglan) and prochlorperazine (Compazine). Opioid withdrawal. Barbiturates withdrawal. Cocaine withdrawal (Mostly in heavy and long-term users). Benzodiazepines , Alcohol and Amphetamines withdrawal (Less common). Psychogenic mechanisms such as anxiety or distress.

The 2006 UK study by Healy, Herxheimer, and Menkes observed that akathisia is often miscoded in antidepressant clinical trials as "agitation, emotional lability, and hyperkinesis (overactivity)".[5] The study further points out that misdiagnosis of akathisia as simple motor restlessness occurs, but that this is more properly classed as dyskinesia. Healy, et al., further show links between antidepressant-induced akathisia and violence, including suicide, as akathisia can "exacerbate psychopathology." The study goes on to state that there is extensive clinical evidence correlating akathisia with SSRI use, showing that approximately ten times as many patients on SSRIs as those on placebos showed symptoms severe enough to drop out of a trial (5.0% compared to 0.5%).

[edit] Treatment

Akathisia can be reduced by withdrawing or decreasing the dose of the causative agent, or by administering other drugs. The first-line treatment of akathisia is usually a beta-blocker, such as propranolol or metoprolol. Benzodiazepines such as clonazepam are also effective. The antihistamine cyproheptadine is also effective, though with shorter effect than beta blockers. Benztropine and Trihexyphenidyl can also be used to treat this condition.

One study showed that vitamin B6 is effective for the treatment of neuroleptic-induced akathisia.[9]

N Acetyl Cysteine also showed a positive effect on akathisia in an RCT.[

Hypokinesia refers to decreased bodily movement.[1] It is associated with basal ganglia diseases (such as Parkinson's disease), mental health disorders and prolonged inactivity due to illness, amongst other diseases.

Hypokinesia

describes a spectrum of disorders:

Akinesia (a-, "without", kinisi, "motion") is the inability to initiate movement due to difficulty selecting and/or activating motor programs in the central nervous system. Common in severe cases of Parkinson's disease, akinesia is a result of severely diminished dopaminergic cell activity in the direct pathway of movement.

Bradykinesia (brady-, "slow", kinisi, "motion") is characterized by slowness of movement and has been linked to Parkinson's disease and other disorders of the basal ganglia. Rather than being a slowness in initiation (akinesia), bradykinesia describes a slowness in the execution of movement. It is one of the 3 key symptoms of parkinsonism, which are bradykinesia, tremor and rigidity. Bradykinesia is also the cause of what is normally referred to as "stone face" (expressionless face) among those with Parkinson's. A very detailed explanation of this topic can be found at http://www.wemove.org/bradykinesia.

Freezing is characterized by an inability to move muscles in any desired direction.

Rigidity results when there is an increase in muscle tone that causes resistance to passive movement throughout the whole range of motion. There are different types of rigidity. The form just described is the so-called 'lead-pipe' rigidity seen especially in Parkinson's disease. 'Cogwheel' rigidity is a combination of rigidity and tremor which presents as a jerky resistance to passive movement. Spasticity is a special form of rigidity that is present only at the start of passive movement. It is rate dependent and only elicited upon a high speed movement. These various forms of rigidity can be seen in different forms of movement disorders, such as Parkinson's disease.

Postural instability : loss of ability to maintain an upright posture.

Athetosis is a continuous stream of slow, sinuous, writhing movements, typically of the hands and feet. Movements typical to athetosis are sometimes called athetoid movements. It is said to be caused by damage to the corpus striatum of the brain - specifically to the putamen. It can also be caused by a lesion of the motor thalamus.[citation

needed]

Athetosis is to be distinguished from pseudoathetosis, which is abnormal writhing movement, usually of the fingers, occurring when the eyes are closed, caused by a failure of joint position sense (proprioception), for example in peripheral neuropathy.

Ataxia (from Greek α- [used as a negative prefix] + -τάξις [order], meaning "lack of order") is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum. Several possible causes exist for these patterns of neurological dysfunction. The term "dystaxia" is a rarely-used synonym.

Types

[edit] Cerebellar

The term cerebellar ataxia is employed to indicate ataxia that is due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits, such as antagonist hypotonia, asynergy, dysmetria, dyschronometria, and dysdiadochokinesia. How and where these abnormalities manifest themselves depends on which cerebellar structures have been damaged, and whether the lesion is bilateral or unilateral.

Dysfunction of the vestibulocerebellum impairs the balance and the control of eye movements. This presents itself with postural instability, in which the person tends to separate his/her feet upon standing, in order to gain a wider base and to avoid bodily oscillations (especially forward-backward ones). The instability is therefore worsened when standing with the feet together, regardless of whether the eyes are open or closed. This is a negative Romberg's test, or more accurately, it denotes the individual's inability to carry out the test, because the individual feels unstable even with open eyes).

Dysfunction of the spinocerebellum presents itself with a wide-based "drunken sailor" gait, characterised by uncertain start and stop, lateral deviations, and unequal steps. This part of the cerebellum regulates body and limb movements.

Dysfunction of the cerebrocerebellum presents with disturbances in carrying out voluntary, planned movements. These include:

o intention tremor (coarse trembling, accentuated over the execution of voluntary movements, possibly involving the head and eyes as well as the limbs and torso);

o peculiar writing abnormalities (large, unequal letters, irregular underlining);

o a peculiar pattern of dysarthria (slurred speech, sometimes characterised by explosive variations in voice intensity despite a regular rhythm).

[edit] Sensory

The term sensory ataxia is employed to indicate ataxia due to loss of proprioception - the loss of sensitivity to the positions of joint and body parts. This is generally caused by dysfunction of the dorsal columns of the spinal cord, because they carry proprioceptive information up to the brain. In some cases, the cause of sensory ataxia may instead be dysfunction of the various parts of the brain which receive positional information, including the cerebellum, thalamus, and parietal lobes.

Sensory ataxia presents itself with an unsteady "stomping" gait with heavy heel strikes, as well as a postural instability that is usually worsened when the lack of proprioceptive input cannot be compensated for by visual input, such as in poorly lit environments.

Physicians can find evidence of sensory ataxia during physical examination by having the patient stand with his/her feet together and eyes shut. In affected patients, this will cause the instability to worsen markedly, producing wide oscillations and possibly a fall. This is

called a positive Romberg's test. Worsening of the finger-pointing test with the eyes closed is another feature of sensory ataxia. Also, when the patient is standing with arms and hands extended toward the physician, if the eyes are closed, the patient's finger will tend to "fall down" and then be restored to the horizontal extended position by sudden muscular contractions (the "ataxic hand").

[edit] Vestibular

The term vestibular ataxia is employed to indicate ataxia due to dysfunction of the vestibular system, which in acute and unilateral cases is associated with prominent vertigo, nausea and vomiting. In slow-onset, chronic bilateral cases of vestibular dysfunction, these characteristic manifestations may be absent, and dysequilibrium may be the sole presentation.

[edit] Causes

The three types of ataxia have overlapping causes, and therefore can either coexist or occur in isolation.

[edit] Focal lesions

Any type of focal lesion of the central nervous system (such as stroke, brain tumour, multiple sclerosis) will cause the type of ataxia corresponding to the site of the lesion: cerebellar if in the cerebellum, sensory if in the dorsal spinal cord (and rarely in the thalamus or parietal lobe), vestibular if in the vestibular system (including the vestibular areas of the cerebral cortex).

[edit] Exogenous substances

Exogenous substances that cause ataxia mainly do so because they have a depressant effect on central nervous system function. The most common example is ethanol, which is capable of causing reversible cerebellar and vestibular ataxia. Other examples include various prescription drugs (e.g. most antiepileptic drugs have cerebellar ataxia as a possible adverse effect), cannabis ingestion[2] and various other recreational drugs (e.g. ketamine, PCP or dextromethorphan, all of which are NMDA receptor antagonists that produce a dissociative state at high doses). Exposure to high levels of methylmercury, through consumption of fish with high mercury concentrations, is also a known cause of ataxia and other neurological disorders[3]

[edit] Vitamin B12 deficiency

Vitamin B12 deficiency may cause, among several neurological abnormalities, overlapping cerebellar and sensory ataxia.

[edit] Causes of isolated sensory ataxia

Peripheral neuropathies may cause generalised or localised sensory ataxia (e.g. a limb only) depending on the extent of the neuropathic involvement. Spinal disorders of various types may cause sensory ataxia from the lesioned level below, when they involve the dorsal columns.

[edit] Non-hereditary cerebellar degeneration

Non-hereditary causes of cerebellar degeneration include chronic ethanol abuse, paraneoplastic cerebellar degeneration, high altitude cerebral oedema, coeliac disease, normal pressure hydrocephalus and cerebellitis.

[edit] Hereditary ataxias

Ataxia may depend on hereditary disorders consisting of degeneration of the cerebellum and/or of the spine; most cases feature both to some extent, and therefore present with overlapping cerebellar and sensory ataxia, even though one is often more evident than the other. Hereditary disorders causing ataxia include autosomal dominant ones such as spinocerebellar ataxia, episodic ataxia, and dentatorubropallidoluysian atrophy, as well as autosomal recessive disorders such as Friedreich's ataxia (sensory and cerebellar, with the former predominating) and Niemann Pick disease, ataxia-telangiectasia (sensory and cerebellar, with the latter predominating), and abetalipoproteinaemia. An example of X-linked ataxic condition is the rare fragile X-associated tremor/ataxia syndrome.

[edit] Arnold-Chiari Malformation

Arnold-Chiari malformation is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils and the medulla through the foramen magnum, sometimes causing hydrocephalus as a result of obstruction of cerebrospinal fluid outflow.

[edit] Treatment

The movement disorders related to ataxia are primarily treated with physical therapy. As ataxia involves a loss of coordinated and efficient action of stabilising muscles in the trunk, exercise training typically includes a focus on stability exercise. There is often an array of other motor deficits requiring exercise treatment including weakness, balance impairment and decreased endurance. It is also possible that treatment will include strategies to manage difficulties with everyday activities, such as a cane or walker to decrease the risk of falls associated with a balance impairment, or prescription of a wheelchair.

[edit] Other uses of the term

The term "ataxia" is sometimes used in a broader sense to indicate lack of coordination in some physiological process. Examples include optic ataxia (lack of coordination

between visual inputs and hand movements, resulting in inability to reach and grab objects, usually part of Balint's syndrome, but can be seen in isolation with injuries to the superior parietal lobule, as it represents a disconnection between visual-association cortex and the frontal premotor and motor cortex[4]), and ataxic respiration (lack of coordination in respiratory movements, usually due to dysfunction of the respiratory centres in the medulla oblongata).

horeia (or chorea) is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία (=dance), see choreia (dance)), as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.

The term hemichoreia refers to choreia of one side of the body, such as choreia of one arm and not both (comparable to hemiballismus).

Presentation

Choreia is characterized by brief, quasi-purposeful, irregular contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next.

These 'dance-like' movements of choreia (from the same root word as "choreography") often occur with athetosis, which adds twisting and writhing movements.

This condition is portrayed by Edward Norton's character in the film The Score, especially when he says "OK bye bye"

[edit] Causes

Choreia can occur in a variety of conditions and disorders.

Choreia is a primary feature of Huntington's disease, a progressive neurological disorder.

Twenty percent of children and adolescents with rheumatic fever develop Sydenham's chorea as a complication.

Choreia gravidarum is rare type of choreia which is a complication of pregnancy. Choreia may also be caused by drugs (levodopa, anti-convulsants, anti-

psychotics), metabolic disorders, endocrine disorders, and vascular incidents. Ataxia telangiectasia Wilson's disease , a genetic disorder that leads to toxic levels of copper in the body

[edit] Ballism

When choreia is serious, slight movements will become thrashing motions; this form of severe choreia is referred to as ballism. Walking may become peculiar, and include odd postures and leg movements. Unlike ataxia and dystonia, which affect the quality of voluntary movements or parkinsonism, which is a hindrance of voluntary movements, the movements of choreia and ballism occur on their own, without conscious effort.

[edit] Treatment

There is no standard course of treatment for choreia. Treatment depends on the type of choreia and the associated disease. Although there are many drugs that can control it, there is no known cure.

Form Treatment

Huntington's-relatedA common treatment is dopaminergic antagonists, although treatment is largely supportive.

Sydenham's choreaHaloperidol, carbamazepine and valproic acid.Usually involves antibiotic drugs to treat the infection, followed by drug therapy to prevent recurrence.

Choreia gravidarumhaloperidol [1] [2] [3] , chlorpromazine alone or in combination with diazepam, also pimozide can also be used.

Wilson's diseaseReducing levels of copper in the body using D-penicillinamine, trientine hydrochloride, tetrathiomolybdate, and other chelating agents

Drug-induced choreia Adjusting medication dosages.Metabolic and endocrine-related choreias

Treated according to their causes.

Sydenham's chorea or Chorea minor (also known as "Saint Vitus' Dance")[1] is a disease characterized by rapid, uncoordinated jerking movements affecting primarily the face, feet and hands. Sydenham's chorea (SC) results from childhood infection with Group A beta-hemolytic Streptococci [2] and is reported to occur in 20-30% of patients with acute rheumatic fever (ARF). The disease is usually latent, occurring up to 6 months after the acute infection, but may occasionally be the presenting symptom of RF. SC is more common in females than males and most patients are children, below 18 years of age. Adult onset of SC is comparatively rare and most of the adult cases are associated with exacerbation of chorea following childhood SC.

It is named for British physician Thomas Sydenham, (1624–1689).[3][4] The alternate eponym, Saint Vitus' dance, is in reference to Saint Vitus, a Christian saint who was persecuted by Roman emperors and died as a martyr in AD 303. Saint Vitus is considered to be the patron saint of dancers, with the eponym given as homage to the manic dancing that historically took place in front of his statue during the feast of Saint Vitus in Germanic and Latvian cultures.[5]

Characteristics

SC is characterised by the acute onset (sometimes a few hours) of motor symptoms, classically chorea, usually affecting all limbs. Other motor symptoms include facial grimacing, hypotonia, loss of fine motor control and a gait disturbance. Fifty percent of patients with acute SC spontaneously recover after 2 to 6 months whilst mild or moderate chorea or other motor symptoms can persist for up to and over 2 years in some cases (for example a patient in the UK who has suffered the illness since 1999)[citation needed]. Sydenham's is also associated with psychiatric symptoms with obsessive compulsive disorder being the most frequent manifestation. The PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections) syndrome is similar, but is not characterized by Sydenham's motor dysfunction, but presenting with tics and/or with psychological components (OCD) and much sooner, days to week after GABHS infection rather than 6–9 months.[6] It is related to other illnesses such as Lupus and Tourette's.

Movements cease during sleep, and the disease usually resolves after several months. It is associated with post-streptococcal rheumatic fever, pregnancy, hyperthyroidism, and systemic lupus erythematosus.

Neurologic symptoms of SC include behavior change, dysarthria, gait change, loss of fine and gross motor control with resultant deterioration of handwriting, headache, slowed cognition, facial grimacing, fidgetiness and hypotonia [7] [8] . Nonneurologic manifestations of ARF are carditis, arthritis, erythema marginatum, and subcutaneous nodules [7] .

[edit] Causes

A major manifestation of ARF, Sydenham's chorea is a result of an autoimmune response that occurs following infection by group A β-hemolytic streptococci[9] that destroys cells in the basal ganglia [8] [9] [10] . The incidence of ARF and rheumatic heart disease (RHD) is not declining. Recent figures quote the incidence of ARF as 0.6 - 0.7/1 000 population in the USA and Japan compared with 15 - 21/1 000 population in Asia and Africa.[3] The prevalence of ARF and SC has declined progressively in developed countries over the last decades[11][12]. There are many causes of childhood chorea, including cerebrovascular accidents, collagen vascular diseases, drug intoxication, hyperthyroidism, Wilson's disease, Huntington's disease, and infectious agents[7].

[edit] Treatment or Management

Treatment of SC is based on the following three principles:

1. The first tenet of treatment is to eliminate the streptococcus at a primary, secondary and tertiary level. Strategies involve the adequate treatment of throat and skin infections, with a 10-day course of penicillin when SC is newly diagnosed, followed by long-term penicillin prophylaxis. Behavioural and

emotional changes may precede the movement disorders, in a previously well child.

2. Treatment of movement disorders. Therapeutic efforts are limited to palliation of the movement disorders. Haloperidol is frequently used because of its dopaminergic effect as described above. It has serious potential side-effects, e.g. tardive dyskinesia. In a study conducted at the RFC, 25 out of 39 patients on haloperidol reported side-effects severe enough to cause the physician or parent to discontinue treatment or reduce the dose. Other medications which have been used to control the movements include pimozide, clonidine, valproic acid, carbamazepine and phenobarbitone.

3. Immunomodulatory interventions include steroids, intravenous immunoglobulins, and plasma exchange. Patients may benefit from treatment with steroids; controlled clinical trials are indicated to explore this further.

ydenham's chorea or Chorea minor (also known as "Saint Vitus' Dance")[1] is a disease characterized by rapid, uncoordinated jerking movements affecting primarily the face, feet and hands. Sydenham's chorea (SC) results from childhood infection with Group A beta-hemolytic Streptococci [2] and is reported to occur in 20-30% of patients with acute rheumatic fever (ARF). The disease is usually latent, occurring up to 6 months after the acute infection, but may occasionally be the presenting symptom of RF. SC is more common in females than males and most patients are children, below 18 years of age. Adult onset of SC is comparatively rare and most of the adult cases are associated with exacerbation of chorea following childhood SC.

It is named for British physician Thomas Sydenham, (1624–1689).[3][4] The alternate eponym, Saint Vitus' dance, is in reference to Saint Vitus, a Christian saint who was persecuted by Roman emperors and died as a martyr in AD 303. Saint Vitus is considered to be the patron saint of dancers, with the eponym given as homage to the manic dancing that historically took place in front of his statue during the feast of Saint Vitus in Germanic and Latvian cultures.[

Characteristics

SC is characterised by the acute onset (sometimes a few hours) of motor symptoms, classically chorea, usually affecting all limbs. Other motor symptoms include facial grimacing, hypotonia, loss of fine motor control and a gait disturbance. Fifty percent of patients with acute SC spontaneously recover after 2 to 6 months whilst mild or moderate chorea or other motor symptoms can persist for up to and over 2 years in some cases (for example a patient in the UK who has suffered the illness since 1999)[citation needed]. Sydenham's is also associated with psychiatric symptoms with obsessive compulsive disorder being the most frequent manifestation. The PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections) syndrome is similar, but is not characterized by Sydenham's motor dysfunction, but presenting with tics and/or with psychological components (OCD) and much sooner, days to week after GABHS infection rather than 6–9 months.[6] It is related to other illnesses such as Lupus and Tourette's.

Movements cease during sleep, and the disease usually resolves after several months. It is associated with post-streptococcal rheumatic fever, pregnancy, hyperthyroidism, and systemic lupus erythematosus.

Neurologic symptoms of SC include behavior change, dysarthria, gait change, loss of fine and gross motor control with resultant deterioration of handwriting, headache, slowed cognition, facial grimacing, fidgetiness and hypotonia [7] [8] . Nonneurologic manifestations of ARF are carditis, arthritis, erythema marginatum, and subcutaneous nodules [7] .

[edit] Causes

A major manifestation of ARF, Sydenham's chorea is a result of an autoimmune response that occurs following infection by group A β-hemolytic streptococci[9] that destroys cells in the basal ganglia [8] [9] [10] . The incidence of ARF and rheumatic heart disease (RHD) is not declining. Recent figures quote the incidence of ARF as 0.6 - 0.7/1 000 population in the USA and Japan compared with 15 - 21/1 000 population in Asia and Africa.[3] The prevalence of ARF and SC has declined progressively in developed countries over the last decades[11][12]. There are many causes of childhood chorea, including cerebrovascular accidents, collagen vascular diseases, drug intoxication, hyperthyroidism, Wilson's disease, Huntington's disease, and infectious agents[7].

[edit] Treatment or Management

Treatment of SC is based on the following three principles:

1. The first tenet of treatment is to eliminate the streptococcus at a primary, secondary and tertiary level. Strategies involve the adequate treatment of throat and skin infections, with a 10-day course of penicillin when SC is newly diagnosed, followed by long-term penicillin prophylaxis. Behavioural and emotional changes may precede the movement disorders, in a previously well child.

2. Treatment of movement disorders. Therapeutic efforts are limited to palliation of the movement disorders. Haloperidol is frequently used because of its dopaminergic effect as described above. It has serious potential side-effects, e.g. tardive dyskinesia. In a study conducted at the RFC, 25 out of 39 patients on haloperidol reported side-effects severe enough to cause the physician or parent to discontinue treatment or reduce the dose. Other medications which have been used to control the movements include pimozide, clonidine, valproic acid, carbamazepine and phenobarbitone.

3. Immunomodulatory interventions include steroids, intravenous immunoglobulins, and plasma exchange. Patients may benefit from treatment with steroids; controlled clinical trials are indicated to explore this further.

Huntington's disease, chorea, or disorder (HD), is a progressive neurodegenerative genetic disorder, which affects muscle coordination and leads to cognitive decline and

dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea and is much more common in people of Western European descent than in those from Asia or Africa. The disease is caused by an autosomal dominant mutation on either of an individual's two copies of a gene called Huntingtin, which means any child of an affected parent has a 50% risk of inheriting the disease. In rare situations where both parents have an affected gene, or either parent has two affected copies, this risk is greatly increased. Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid or Westphal variant HD.

The Huntingtin gene normally provides the genetic information for a protein that is also called "Huntingtin". The mutation of the Huntingtin gene codes for a different form of the protein, whose presence results in gradual damage to specific areas of the brain. The exact way this happens is not fully understood. Genetic testing can be performed at any stage of development, even before the onset of symptoms. This raises several ethical debates regarding the age at which an individual is considered mature enough to choose testing, the right of parents to test their children, and confidentiality and disclosure of test results. Genetic counseling has developed to inform and aid individuals considering genetic testing and has become a model for other genetically dominant diseases.

The exact way HD affects an individual varies and can differ even between members of the same family, but the symptoms progress predictably for most individuals. The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral and psychiatric problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult, and mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years after symptoms begin. There is no cure for HD, and full-time care is required in the later stages of the disease, but there are emerging treatments to relieve some of its symptoms.

Self-help support organizations, first founded in the 1960s and increasing in number, have been working to increase public awareness, to provide support for individuals and their families, and to promote research. The Hereditary Disease Foundation, a research group born out of the first support organization, was instrumental in finding the gene in 1993. Since that time there have been important discoveries every few years and understanding of the disease is improving. Current research directions include determining the exact mechanism of the disease, improving animal models to expedite research, clinical trials of pharmaceuticals to treat symptoms or slow the progression of the disease, and studying procedures such as stem cell therapy with the goal of repairing damage caused by the disease.

Signs and symptoms

Symptoms of Huntington's disease commonly become noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy.[1][2] In the early stages, there are subtle changes in personality, cognition, or physical skills.[1] The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at the earlier stages.[1] Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between individuals.[3][4]

The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.[1] Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements.[1] These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.[3] The clear appearance of symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder progresses.[5] These are signs that the system in the brain that is responsible for movement is affected.[6] Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing and speaking.[5] Eating difficulties commonly cause weight loss and may lead to malnutrition.[7][8] Sleep disturbances are also associated symptoms.[9] Juvenile HD differs from these symptoms in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. Seizures are also a common symptom of this form of HD.[5]

Reported prevalences of behavioral and psychiatric symptoms in Huntington's disease[10]

Irritability 38–73%Apathy 34–76%Anxiety 34–61%

Depressed mood 33–69%Obsessive and compulsive 10–52%

Psychotic 3–11%

Cognitive abilities are impaired progressively.[6] Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.[6] As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one's life), procedural (memory of the body of how to perform an activity) and working memory.[6] Cognitive problems tend to worsen over time, ultimately leading to dementia.[6] This pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical effects of cortical dementias e.g. Alzheimer's disease.[6]

Reported neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and

hypersexuality.[10] Difficulties in recognizing other people's negative expressions have also been observed.[6] Prevalence of these symptoms is also highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%.[10] For many sufferers and their families these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalisation.[10] Suicidal thoughts and suicide attempts are more common than in the general population.[1]

Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis and testicular atrophy.[11]

[edit] Genetics

All humans have the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt). Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant: mutation of either of a person's HTT genes causes the disease. It is not inherited according to sex, but the length of the repeated section of the gene, and hence its severity, can be influenced by the sex of the affected parent.[12]

[edit] Genetic mutation

HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range.[13] The HTT gene is located on the short arm of chromosome 4 [13] at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat.[13] CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.[14]

Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[13]

Repeat count Classification Disease status

<28 Normal Unaffected

28–35 Intermediate Unaffected

36–40 Reduced Penetrance +/- Affected

>40 Full Penetrance Affected

Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin.[13] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.[13] This altered form, called mHtt (mutant Htt), increases the decay rate of certain types of neuron. Regions of the brain have differing amounts and reliance on these type of neurons, and are affected accordingly.[5] Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD.[13] 36–40 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases the onset may be so late that symptoms are never noticed.[15] With very large repeat counts, HD has full penetrance and can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.[16]

[edit] Inheritance

Huntington's disease is inherited in an autosomal dominant fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of gender, and the gene does not skip generations.

Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent.[1] Since penetrance of the mutation is very high those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.[17]

Trinucleotide CAG repeats over 28 are unstable during replication and this instability increases with the number of repeats present.[15] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.[13] This causes the number of repeats to change in successive

generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.[13] Such increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.[13] Instability is greater in spermatogenesis than oogenesis;[13] maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.[13][18] It is rare for Huntington's disease to be caused by a new mutation, where neither parent has over 36 CAG repeats.[19]

Individuals with both genes affected are rare, except in large consanguineous families.[20] For some time HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression,[21] but it has since been found that it can affect the phenotype and the rate of progression.[13][20] Offspring of an individual who has two affected genes will inherit one of them and therefore definitely inherit the disease. Offspring where both parents have one affected gene have a 75% risk of inheriting HD, including a 25% risk of inheriting two affected genes.[17] Identical twins, who have inherited the same affected gene, typically have differing ages of onset and symptoms.[20]

[edit] Mechanism

The Htt protein interacts with over 100 other proteins, and appears to have multiple biological functions.[22] The behavior of mutated mHtt protein is not completely understood, but it is toxic to certain types of cells, particularly in the brain. Damage mainly occurs in the striatum, but as the disease progresses, other areas of the brain are also significantly affected. As the damage accumulates, symptoms associated with the functions of these brain areas appear. Planning and modulating movement are the main functions of the striatum, and difficulties with these are initial symptoms.[12]

[edit] Htt function

See also: Huntingtin

Htt is expressed in all mammalian cells. The highest concentrations are found in the brain and testes, with moderate amounts in the liver, heart, and lungs.[12] The function of Htt in humans is unclear. It interacts with proteins which are involved in transcription, cell signaling and intracellular transporting.[12][23] In animals genetically modified to exhibit HD, several functions of Htt have been found.[24] In these animals, Htt is important for embryonic development, as its absence is related to embryonic death. It also acts as an anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor, a protein which protects neurons and regulates their creation during neurogenesis. Htt also facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription.[24] If the expression of Htt is increased and more Htt produced, brain cell survival is improved and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting characteristics

are more typical of the presence of mHtt.[24] In humans the disruption of the normal gene does not cause the disease.[12] It is currently concluded that the disease is not caused by inadequate production of Htt, but by a gain of toxic function of mHtt.[12]

[edit] Cellular changes due to mHtt

A microscope image of a neuron with inclusion (stained orange) caused by HD, image width 250 µm

There are multiple cellular changes through which the toxic function of mHtt may manifest and produce the HD pathology.[25][26] During the biological process of posttranslational modification of mHtt, cleavage of the protein can leave behind shorter fragments constituted of parts of the polyglutamine expansion.[25] The polar nature of glutamate causes interactions with other proteins when glutamate is overabundant in Htt proteins. Thus, the Htt molecule strands will form hydrogen bonds with one another, forming a protein aggregate rather then folding into functional proteins. [27] Over time, the aggregates accumulate, ultimately interfering with neuron function because these fragments can then misfold and coalesce, in a process called protein aggregation, to form inclusion bodies within cells.[25] [27] Neuronal inclusions run indirect interference. The excess protein aggregates clump together at axons and dendrites in neurons which mechanically stops the transmission of neurotransmitters because vesicles (filled with neurotransmitters) can no longer move through the cytoskeleton. Ultimately, over time, less and less neurotransmitters are available for release in signaling other neurons as the neuronal inclusions grow. [27] Inclusion bodies have been found in both the cell nucleus and cytoplasm.[25] Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.[25]

Several pathways by which mHtt may cause cell death have been identified. These include: effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases, which play a role in the process of removing cells; the toxic effects of glutamate on nerve cells; impairment of energy production within cells; and effects on the expression of genes. The cytotoxic effects of mHtt are strongly enhanced by interactions with a protein called Rhes, which is expressed mainly in the

striatum.[28] Rhes was found to induce sumoylation of mHtt, which causes the protein clumps to disaggregate—studies in cell culture showed that the clumps were much less toxic than the disaggregated form.[28]

An additional theory that explains another way cell function may be disrupted by HD proposes that damage to mitochondria in striatal cells (numerous accounts of mitochondrial metabolism deficiency have been found) and the interactions of the altered huntingtin protein with numerous proteins in neurons leads to an increased vulnerability of glutamine, which, in large amounts, has been found to be an excitotoxin. Excitotoxins may cause damage to numerous cellular structures. Although glutamine isn't found in excessively high amounts, its been postulated that because of the increased vulnerability, even normal amounts glutamine can cause excitotoxins to be expressed. Furthermore, the increase in sensitivity turn on capases are activated by the repeat expansion of polyglutamine and the increase in sensitivity. The huntingtin protein is cleaved into tiny pieces by capases; these nuclear aggregates disrupt transcription by interfering with the production of proteins by "slipping" into the nucleus of the neuron.[29][30] Unfortunately, the cellular stress caused by the interference causes more huntingtin to be broken up until apoptosis occurs.[29]

[edit] Macroscopic changes due to mHtt

Area of the brain damaged by Huntington's disease – striatum (shown in purple)

HD affects specific areas of the brain. The most prominent early effects are in a part of the basal ganglia called the neostriatum, which is composed of the caudate nucleus and putamen.[12] Other areas affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, the hippocampus, purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.[13] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.[13]

Striatal spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal pallidum being less affected.[13][31] HD also causes an abnormal increase in astrocytes.[32]

The basal ganglia—the part of the brain most prominently affected by HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system [6] and the motor circuit.[33] The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends

a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD.[33]

There are two types of way the basal ganglia may be damaged: directly and indirectly. In the direct pathway, less neurotransmitters are sent the internal globus pallidus (IGP), which in turn comprehends this as a decrease in inhibition, thereby releasing a greater amount of neurotransmitters then normal. The thalamus, which receives a greater number of neurotransmitters, becomes inhibited, thus sending less neurotransmitters to the motor cortex. Ultimately, the motor cortex is understimulated and movements are slower than usual. The indirect pathway starts with the external globus pallidus receiving a lower number of neurotransmitters, and in turn, responding to this decrease as a signal of less inhibition, releases a more neurotransmitters. The subthalamic nuclei (STN), which receives the signals from the external globus pallidus, releases fewer neurotransmitters to the IGP in response to the increase of neurotransmitters received. The IGP is now considerably inhibited because the job of the STN is to excite the IGP and therefore, the IGP releases fewer neurotransmitters. In this context, the reception of less neurotransmitters by the thalamus is perceived as less inhibition. Finally, the motor cortex receives more neurotransmitters and is overstimulated, causing the jerky movements usual in chorea. Since there are two different types of neurons in the striatum, a different neuron, with different axons and dendrites targeted, is stimulated in each pathway (though neurotransmitter GABA is used in both) and thus both can run at the same time. The indirect pathway is generally affected first, which is why chorea is among the first symptoms, but eventually, both types of neurons die off and movement is severely limited. [29]

[edit] Transcriptional Dysregulation

CREB-binding protein (CBP), a transcription factor, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.[30] Futhermore, the amino acids that form CBP include a strip 18 glutamines. Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the Htt chain and CBP gets pulled away from its typical location next to the nucleus.[34] Specifically, CRB contains a acetyltransferase domain that, in an experiment performed by Steffan and colleagues, showed that a Htt exon 1 with 51 glutamines binded to this domain in CBP.[30] Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP. [34] Plus, when CBP is overexpressed, polyglutamine-induced death diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.[30]

[edit] Diagnosis

Medical diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease.[1] Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure, and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family planning decisions, relatives and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.[12]

[edit] Clinical

Coronal section from a MR brain scan of a patient with HD showing atrophy of the heads of the caudate nuclei, enlargement of the frontal horns of the lateral ventricles, and generalised cortical atrophy.[35]

A physical examination, sometimes combined with a psychological examination, can determine whether the onset of the disease has begun.[1] Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or psychiatric symptoms are rarely the first diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.[36][37] Medical imaging, such as computerized tomography (CT) and magnetic resonance imaging (MRI), only shows visible cerebral atrophy in the advanced stages of the disease. Functional neuroimaging techniques such as fMRI and PET can show changes in brain activity before the onset of physical symptoms.[13]

[edit] Genetic

See also: Genetic testing

Because HD is dominant, there is a strong motivation for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the HTT alleles.[38] A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.[13]

A pre-symptomatic test is a life-changing event and a very personal decision.[13] The main reason given for choosing testing for HD is to aid in career and family decisions.[13] Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because there is no treatment.[13] A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result.[12] Irrespective of the result, stress levels have been found to be lower two years after being tested, but the risk of suicide is increased after a positive test result.[12] Individuals found to have not inherited the disorder may experience survivor guilt with regard to family members who are affected.[12] Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.[12] Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process.[39] Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxias.[12][40][41] Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimer's disease and breast cancer.[40]

[edit] Embryonic

Embryos produced using in vitro fertilisation may be genetically tested for HD using preimplantation genetic diagnosis. This technique, where a single cell is extracted from a 4 to 8 cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos with affected HTT genes are not implanted, and therefore any offspring will not inherit the disease. It is also possible to obtain a prenatal diagnosis for an embryo or fetus in the womb.[42]

[edit] Differential diagnosis

About 90% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called HD-like disorders.[5][43] Most of these other disorders are collectively labelled HD-like (HDL).[43] The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the prion protein gene

(HDL1), the junctophilin 3 gene (HDL2), a recessively inherited HTT gene (HDL3—only found in one family and poorly understood), and the gene encoding the TATA box-binding protein (HDL4/SCA17).[43] Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy.[43] There are also autosomal recessive disorders that resemble sporadic cases of HD. Main examples are chorea acanthocytosis, pantothenate kinase-associated neurodegeneration and X-linked McLeod syndrome.[43]

[edit] Management

Chemical structure of tetrabenazine, an approved compound for the management of chorea in HD

There is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms.[44] For many of these treatments, comprehensive clinical trials to confirm their effectiveness in treating symptoms of HD specifically are incomplete.[45][46] As the disease progresses and a person's ability to tend to their own needs reduces, carefully managed multidisciplinary caregiving becomes increasingly necessary.[45]

Tetrabenazine was developed specifically to reduce the severity of chorea in HD,[45] it was approved in 2008 for this use in the US.[47] Other drugs that help to reduce chorea include neuroleptics and benzodiazepines.[2] Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results.[48] Hypokinesia and rigidity can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid.[2]

Psychiatric symptoms can be treated with medications similar to those used in the general population.[45][46] Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotic drugs are recommended for psychosis and behavioural problems.[46]

Weight loss and eating difficulties due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances.[45] Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow.[45] Reminding the patient to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.[45] If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available.

This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the risk of aspirating food and provides better nutritional management.[49]

Although there have been relatively few studies of exercises and therapies that help rehabilitate cognitive symptoms of HD, there is some evidence for the usefulness of physical therapy, occupational therapy, and speech therapy. However, more rigorous studies are needed for health authorities to endorse them.[50] A multidisciplinary approach may be important to limit disability.[51] The families of individuals, who have inherited or are at risk of inheriting HD, have generations of experience of HD which may be outdated and lack knowledge of recent breakthroughs and improvements in genetic testing, family planning choices, care management, and other considerations. Genetic counseling benefits these individuals by updating their knowledge, dispelling any myths they may have and helping them consider their future options and plans.[12][52]

[edit] Prognosis

The length of the trinucleotide repeat accounts for 60% of the variation in the age of onset and the rate of progression of symptoms. A longer repeat results in an earlier age of onset and a faster progression of symptoms.[13][53] For example, individuals with a trinucleotide repeat greater than sixty repeats often develop the disease before twenty years of age, and those with less than forty repeats may not develop noticeable symptoms.[54] The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.[13]

Life expectancy in HD is generally around 20 years following the onset of visible symptoms.[5] Most of the complications that are life-threatening result from muscle coordination issues, or to a lesser extent from behavioural changes resulting from the decline in cognitive function. The largest risk is pneumonia, which is the cause of death of one-third of those with HD. As the ability to synchronise movements deteriorates, difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD.[5] Suicide is the next greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. It is unclear to what extent suicidal thoughts are influenced by psychiatric symptoms, as they may be considered to be a response of an individual to retain a sense of control of their life or to avoid the later stages of the disease .[55][56][57] Other associated risks include choking, physical injury from falls, and malnutrition.[5]

[edit] Epidemiology

The late onset of Huntington's disease means it does not usually affect reproduction.[12] The worldwide prevalence of HD is 5-10 cases per 100,000 persons,[58][59] but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns.[12] Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seventy per million people, and

is lower in the rest of the world, e.g. one per million people of Asian and African descent.[12] Additionally, some localized areas have a much higher prevalence than their regional average.[12] One of the highest prevalences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to seven thousand per million people.[12][60] Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden.[57] Increased prevalence in some cases occurs due to a local founder effect, a historical migration of carriers into an area of geographic isolation.[57][61] Some of these carriers have been traced back hundreds of years using genealogical studies.[57] Genetic haplotypes can also give clues for the geographic variations of prevalence.[57][62]

Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics and as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.[57][63]

[edit] History

In 1872 George Huntington described the disorder in his first paper "On Chorea" at the age of 22.[64]

The first definite mention of HD was in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described 'a form of chorea, vulgarly called magrums', including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.[65] In 1846 Charles Gorman observed how higher prevalence seemed to occur in localized regions.[65] Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College,[66] Johan Christian Lund also produced an early description in 1860.[65] He specifically noted that in Setesdalen, a secluded area in Norway, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.[67]

The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Unknowingly, Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery of Mendelian inheritance. "Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life

without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.".[64][68] Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described."[65][69] Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community.[65] Great interest was shown by scientists in Europe, including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of the century, much of the research into HD was European in origin.[65] By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.[65]

During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.[65] The English biologist William Bateson used the pedigrees of affected families to establish that HD did have an autosomal dominant inheritance pattern.[66] The strong inheritance pattern prompted several researchers to attempt to trace and connect family members of previous studies, one of whom was Smith Ely Jelliffe.[65] Jelliffe collected information from across New York State and published several articles regarding the genealogy of HD in New England.[70] Jelliffe's research roused the interest of his college friend, Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study of families with HD, and construct their pedigrees, on the East Coast of the United States.[71] Davenport used this information to document the variable age of onset and range of symptoms of HD and make the claim that most cases of HD in the USA could be traced back to a handful of individuals.[71] This research was further embellished in 1932 by P. R. Vessie, who popularised the idea that three brothers who left England in 1630, bound for Boston were the progenators of HD in the USA.[72] The claim that the earliest progenators had been established and eugenic bias of Muncey's, Davenport, and Vessie's work contributed to misunderstandings and prejudice about HD.[66] Muncey and Davenport also popularised the idea that in the past some HD sufferers may have been thought to be possessed by spirits or victims of witchcraft, and were sometimes shunned or exiled by society.[73][74] This idea has not been proven, and there is evidence to the contrary, for example, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.[66][73]

Research into the disorder continued steadily through the 20th century, reaching a major breakthrough in 1983 when the US–Venezuela Huntington's Disease Collaborative Research Project discovered the approximate location of a causal gene.[61] This was the result of an extensive study begun in 1979, focusing on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. Among other innovations, the project developed DNA marking methods which were an important step in making the Human Genome Project possible.[75]

In 1993 the research group isolated the precise causal gene at 4p16.3,[76] making this the first autosomal disease locus found using genetic linkage analysis.[76][77] In the same time

frame, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding's research group on the effects of the gene's length.[78]

Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996, enabled larger scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans, results from experiments are received sooner, speeding research.[79][80] The 1997 discovery that mHtt fragments misfold led to the discovery of the nuclear inclusions they cause.[81] These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.[65][82][83]

movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures.[1] The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning (e.g., lead poisoning) or reaction to pharmaceutical drugs, particularly neuroleptics.[1] Treatment is difficult and has been limited to minimizing the symptoms of the disorder, since there is no cure available.

Classification

[edit] Types of dystonia

Generalized Focal Segmental Intermediate Acute Dystonic Reaction[2]

[edit] Generalized dystonias

Normal birth history and milestones Autosomal dominant childhood onset starts in lower limbs and spreads upwards also known as "idiopathic torsion dystonia" (old terminology "dystonia

musculrum deformans")

[edit] Focal dystonias

Main article: Focal dystonia

These are the most common dystonias and tend to be classified as follows:

Name Location Description

Anismusmuscles of the rectum

Causes painful defecation, constipation; may be complicated by encopresis.

Cervical dystonia (spasmodic torticollis)

muscles of the neck

Causes the head to rotate to one side, to pull down towards the chest, or back, or a combination of these postures.

Blepharospasmmuscles around the eyes

The sufferer experiences rapid blinking of the eyes or even their forced closure causing effective blindness.

Oculogyric crisismuscles of eye and head

An extreme and sustained (usually) upward deviation of the eyes often with convergence causing diplopia. It is frequently associated with backwards and lateral flexion of the neck and either widely opened mouth or jaw clenching. Frequently a result of antiemetics such as the neuroleptics (e.g., prochlorperazine) or metoclopramide.

Oromandibular dystonia

muscles of the jaw and muscles of tongue

Causes distortions of the mouth and tongue.

Spasmodic dysphonia/Laryngeal dystonia

muscles of larynx

Causes the voice to sound broken or reducing it to a whisper.

Focal hand dystonia (also known as musician's or writer's cramp).

single muscle or small group of muscles in the hand

It interferes with activities such as writing or playing a musical instrument by causing involuntary muscular contractions. The condition is sometimes "task-specific," meaning that it is generally only apparent during certain activities. Focal hand dystonia is neurological in origin, and is not due to normal fatigue. The loss of precise muscle control and continuous unintentional movement results in painful cramping and abnormal positioning that makes continued use of the affected body parts impossible.

The combination of blepharospasmodic contractions and oromandibular dystonia is called cranial dystonia or Meige's syndrome.

[edit] Segmental dystonias

Segmental dystonias affect two adjoining parts of the body:

Hemidystonia affects an arm and a leg on one side of the body. Multifocal dystonia affects many different parts of the body. Generalized dystonia affects most of the body, frequently involving the legs and

back.

[edit] Genetic / primary

Name OMIM Gene Locus Alt NameDYT1 (or EOTD)

128100 DYT1 9q34 early-onset torsion dystonia

DYT2 224500 unknown unknownautosomal recessive torsion dystonia

DYT3 314250 TAF1 Xq13 X-linked torsion dystonia

DYT4 128101 unknown unknownautosomal dominant torsion dystonia

DYT5 (or DRD)

128230 GCH114q22.1-q22.2

Dopamine-responsive dystonia

DYT6 602629 THAP1 8p11.21DYT7 602124 unknown 18p Primary cervical dystoniaDYT8 (or PNKD1)

118800 MR1 2q35paroxysmal nonkinesigenic dyskinesia 1

DYT9 601042 possibly KCNA3 [3] 1pepisodic choreoathetosis/spasticity

DYT10 (or EKD1)

128200 unknown16p11.2-q12.1

episodic kinesigenic dyskinesia 1

DYT11 159900 SGCE 7q21 Myoclonic dystoniaDYT12 128235 ATP1A3 19q12-q13.2

DYT13 607671unknown, near D1S2667[4]

1p36.32-p36.13

DYT14See DYT5

DYT15 607488 unknown 18p11[5] Myoclonic dystoniaDYT16 612067 PRKRA 2q31.3

DYT17 612406unknown, near D20S107[6]

20p11.2-q13.12

DYT18 612126 SLC2A1 1p35-p31.3DYT19 (or EKD2)

611031 unknown 16q13-q22.1episodic kinesigenic dyskinesia 2

DYT20 (or PNKD2)

611147 unknown 2q31paroxysmal nonkinesigenic dyskinesia 2

There is a group called myoclonus dystonia or myoclonic dystonia, where some cases are hereditary and have been associated with a missense mutation in the dopamine-D2 receptor. Some of these cases have responded remarkably to alcohol

Symptoms vary according to the kind of dystonia involved. In most cases, dystonia tends to lead to abnormal posturing, particularly on movement. Many sufferers have continuous pain, cramping and relentless muscle spasms due to involuntary muscle movements. Other motor symptoms are possible including lip smacking.[9]

Early symptoms may include loss of precision muscle coordination (sometimes first manifested in declining penmanship, frequent small injuries to the hands, and dropped items), cramping pain with sustained use and trembling. Significant muscle pain and cramping may result from very minor exertions like holding a book and turning pages. It may become difficult to find a comfortable position for arms and legs with even the minor exertions associated with holding arms crossed causing significant pain similar to restless leg syndrome. Affected persons may notice trembling in the diaphragm while breathing, or the need to place hands in pockets, under legs while sitting or under pillows while sleeping to keep them still and to reduce pain. Trembling in the jaw may be felt and heard while lying down, and the constant movement to avoid pain may result in the grinding and wearing down of teeth, or symptoms similar to TMD. The voice may crack frequently or become harsh, triggering frequent throat clearing. Swallowing can become difficult and accompanied by painful cramping.

Electrical sensors (EMG) inserted into affected muscle groups, while painful, can provide a definitive diagnosis by showing pulsating nerve signals being transmitted to the muscles even when they are at rest. The brain appears to signal portions of fibers within the affected muscle groups at a firing speed of about 10 Hz causing them to pulsate, tremble and contort. When called upon to perform an intentional activity, the muscles fatigue very quickly and some portions of the muscle groups do not respond (causing weakness) while other portions over-respond or become rigid (causing micro-tears under load). The symptoms worsen significantly with use, especially in the case of focal dystonia, and a "mirror effect" is often observed in other body parts: use of the right hand may cause pain and cramping in that hand as well as in the other hand and legs that were not being used. Stress, anxiety, lack of sleep, sustained use and cold temperatures can worsen symptoms.

Direct symptoms may be accompanied by secondary effects of the continuous muscle and brain activity, including disturbed sleep patterns, exhaustion, mood swings, mental stress, difficulty concentrating, blurred vision, digestive problems and short temper. People with dystonia may also become depressed and find great difficulty adapting their activities and livelihood to a progressing disability. Side effects from treatment and medications can also present challenges in normal activities.

In some cases, symptoms may progress and then plateau for years, or stop progressing entirely. The progression may be delayed by treatment or adaptive lifestyle changes, while forced continued use may make symptoms progress more rapidly. In others, the symptoms may progress to total disability, making some of the more risky forms of treatment worth considering. In some cases with patients who already have dystonia, a subsequent tramatic injury or the affects of general anethesia during an unrelated surgery can cause the symptoms to progress rapidly.

An accurate diagnosis may be difficult because of the way the disorder manifests itself. Sufferers may be diagnosed as having similar and perhaps related disorders including Parkinson's disease, essential tremor, carpal tunnel syndrome, TMD, Tourette's syndrome, or other neuromuscular movement disorders.

[edit] Causes

The causes of dystonia are not yet known or understood; however, they are categorized as follows on a theoretical basis:

Primary dystonia is suspected to be caused by a pathology of the central nervous system, likely originating in those parts of the brain concerned with motor function, such as the basal ganglia, and the GABA (gamma-aminobutyric acid) producing Purkinje neurons. The precise cause of primary dystonia is unknown. In many cases it may involve some genetic predisposition towards the disorder combined with environmental conditions.

Secondary dystonia refers to dystonia brought on by some identified cause, usually involving brain damage, or by some unidentified cause such as chemical imbalance. Some cases of (particularly focal) dystonia are brought on after trauma, are induced by certain drugs (tardive dystonia), or may be the result of diseases of the nervous system such as Wilson's disease.

Environmental and task-related factors are suspected to trigger the development of focal dystonias because they appear disproportionately in individuals who perform high precision hand movements such as musicians, engineers, architects and artists.

[edit] Treatment

Treatment has been limited to minimizing the symptoms of the disorder as there is yet no successful treatment for its cause. Reducing the types of movements that trigger or worsen dystonic symptoms provides some relief, as does reducing stress, getting plenty of rest, moderate exercise, and relaxation techniques. Various treatments focus on sedating brain functions or blocking nerve communications with the muscles via drugs, neuro-suppression or denervation. All current treatments have negative side effects and risks.

[edit] Physical intervention

Physical therapy can sometimes help with focal dystonia. A structured set of exercises is tailored to help the affected area.

Some focal dystonias have been proven treatable through movement retraining in the Taubman approach, particularly in the case of musicians. However other focal dystonias may not respond and may even be made worse by this treatment.

[edit] Medication

Different medications are tried in an effort to find a combination that is effective for a specific person. Not all people will respond well to the same medications. Medications

that have had positive results in some include: diphenhydramine, benzatropine, anti-Parkinsons agents ( such as trihexyphenidyl), and muscle relaxers (such as diazepam).

Cannabidiol, one of the non-psychoactive cannabinoids found in cannabis sativa, was shown in a 6-week study to have reduced dystonic symptoms in all participants by up to 20-50%. [10][11]

Anticholinergics

Medications such as anticholinergics (benzatropine), which act as inhibitors of the neurotransmitter acetylcholine, may provide some relief. In the case of a acute dystonic reaction, diphenhydramine is sometimes used (though this drug is well known as an antihistamine, in this context it is being used primarily for its anticholinergic role).[2] In the case of Oculogyric crisis, diphenhydramine may be administered with excellent results with symptoms subsiding in a matter of minutes.[citation needed]

Muscle relaxants

Clonazepam, an anti-seizure medicine, is also sometimes prescribed. However, for most their effects are limited and side effects like mental confusion, sedation, mood swings and short-term memory loss occur.

Botulinum toxin injections into affected muscles have proved quite successful in providing some relief for around 3–6 months, depending on the kind of dystonia. Botox injections have the advantage of ready availability (the same form is used for cosmetic surgery) and the effects are not permanent. There is a risk of temporary paralysis of the muscles being injected or the leaking of the toxin into adjacent muscle groups causing weakness or paralysis in them. The injections have to be repeated as the effects wear off and around 15% of recipients will develop immunity to the toxin. There is a Type A and Type B toxin approved for treatment of dystonia; often those that develop resistance to Type A may be able to use Type B.[12]

Noting that botulinum toxin has been shown to have an effect on inhibiting neurogenic inflammation, and evidence suggesting the role of neurogenic inflammation in the pathogenesis of psoriasis, the University of Minnesota has begun a clinical trial to follow up on the observation that patients treated with botulinum toxin for dystonia had dramatic improvement in psoriasis. See: Use of Botulinum Toxin to Treat Psoriasis.

Parkinsonian drugs

Dopamine agonists: One type of dystonia, dopamine-responsive dystonia, can be completely treated with regular doses of L-DOPA in a form such as Sinemet (carbidopa/levodopa). Although this doesn't remove the condition, it does alleviate the symptoms most of the time. (In contrast, dopamine antagonists can sometimes cause dystonia.)

Baclofen

A baclofen pump has been used to treat patients of all ages exhibiting muscle spasticity along with dystonia. The pump delivers baclofen via a catheter to the thecal space surrounding the spinal cord. The pump itself is placed in the abdomen. It can be refilled periodically by access through the skin.[13]

[edit] Surgery

Surgery, such as the denervation of selected muscles, may also provide some relief; however, the destruction of nerves in the limbs or brain is not reversible and should only be considered in the most extreme cases. Recently, the procedure of deep brain stimulation (DBS) has proven successful in a number of cases of severe generalised dystonia.[14] DBS as treatment for medication-refractory dystonia, on the other hand, may increase the risk of suicide in patients. Unfortunately, reference data of patients without DBS therapy are lacking.

A blepharospasm (from Greek: blepharo, eyelid, and spasm, an uncontrolled muscle contraction), is any abnormal contraction or twitch of the eyelid.

It normally refers to benign essential blepharospasm, a focal dystonia—a neurological movement disorder involving involuntary and sustained contractions of the muscles around the eyes. Benign means the condition is not life threatening. Essential indicates that the cause is unknown, but fatigue, stress, or an irritant are possible contributing factors. Symptoms sometimes last for a few days then disappear without treatment, but in most cases the twitching is chronic and persistent, causing lifelong challenges. The symptoms are often severe enough to result in functional blindness. The person's eyelids feel like they are clamping shut and will not open without great effort. Patients have normal eyes, but for periods of time are effectively blind due to their inability to open their eyelids.

Although strides have recently been made in early diagnosis, blepharospasm is often initially mis-diagnosed as allergies or "dry eye syndrome". It is a fairly rare disease, affecting only one in every 20,000 people in the United States.

Symptoms

Excessive blinking and spasming of the eyes, usually characterized by uncontrollable eyelid closure of durations longer than the typical blink reflex, sometimes lasting minutes or even hours.

Uncontrollable contractions or twitches of the eye muscles and surrounding facial area. Some sufferers have twitching symptoms that radiate into the nose, face and sometimes, the neck area.

Dryness of the eyes Sensitivity to the sun and bright light[1]

[edit] Causes

Some causes of blepharospasm have been identified; however, the causes of many cases of blepharospasm remain unknown, although some educated guesses are being made. Some blepharospasm patients have a history of dry eyes and/or light sensitivity, but others report no previous eye problems before onset of initial symptoms.

Some drugs can induce blepharospasm, such as those used to treat Parkinson's disease, as well as sensitivity to hormone treatments, including estrogen-replacement therapy for women going through menopause. Blepharospasm can also be a symptom of acute withdrawal from benzodiazepine dependence. In addition to blepharospasm being a benzodiazepine withdrawal symptom, prolonged use of benzodiazepines can induce blepharospasm and is a known risk factor for the development of blepharospasm.[2]

Blepharospasm may also come from abnormal functioning of the brain basal ganglia. Simultaneous dry eye and dystonias such as Meige's syndrome have been observed. Blepharospasms can be caused by concussions in some rare cases, when a blow to the back of the head damages the basal ganglia.

Stress, anxiety, and fatigue are also known to cause blepharospasm.[3]

[edit] Treatment

Drug therapy: Drug therapy for blepharospasm has proved generally unpredictable and short-termed. Finding an effective regimen for any patient usually requires trial and error over time. In some cases a dietary supplement of magnesium chloride has been found effective.

Botulinum toxin injections (Botox is a widely known example) have been used to induce localized, partial paralysis. Among most sufferers, botolinum toxin injection is the preferred treatment method.[4] Injections are generally administered every three months, with variations based on patient response and usually give almost immediate relief (though for some it may take more than a week) of symptoms from the muscle spasms. Most patients can resume a relatively normal life with regular Botulinum toxin treatments. A minority of sufferers develop minimal or no result from Botox injections and have to find other treatments. For some, Botulinum toxin diminishes in its effectiveness after many years of use. An observed side effect in a minority of patients is ptosis or eyelid droop. Attempts to inject in locations that minimize ptosis can result in diminished ability to control spasms.

Surgery: Patients that do not respond well to medication or botulinum toxin injection are candidates for surgical therapy. The most effective surgical treatment has been protractor myectomy, the removal of muscles responsible for eyelid closure.[5]

Dark glasses are often worn because of sunlight sensitivity, as well as to hide the eyes from others.

Stress management and support groups can help sufferers deal with the disease and prevent social isolation.

Writer's cramp, also called mogigraphia and scrivener's palsy, causes a cramp or spasm affecting certain muscles of the hand and/or fingers[1]. Writer's cramp is a task-specific focal dystonia of the hand [2]. 'Focal' refers to the symptoms being limited to one location (the hand in this case), and 'task-specific' means that symptoms first occur only when the individual engages in a particular activity. Writer's cramp first affects an individual by inhibiting their ability to write

Causes

Although the etiology of writer's cramp is not well known, it was historically believed to be the result of excessive fine motor activity, possibly complicated by a tense or otherwise inappropriate writing technique.[4] More recently, Karin Rosenkranz et al. have suggested that this is not necessarily the case.[5] Musician's cramp (a similar focal dystonia which affects some 1% of instrumentalists[6]) has historically been grouped together with writer's cramp because of this and their common task-specificity. Rosenkranz et al. have more recently identified significant differences between the two populations, however.[7] No matter exactly how it arises, researchers generally agree that these types of focal dystonia are the result of a basal ganglia and/or sensorimotor cortex malfunction in the brain.

Early symptoms may include loss of precision muscle coordination (sometimes first manifested in declining penmanship, frequent small injuries to the hands, dropped items and a noticeable increase in dropped or chipped dishes), cramping pain with sustained use and trembling. Significant muscle pain and cramping may result from very minor exertions like holding a book and turning pages. It may become difficult to find a comfortable position for arms and legs with even the minor exertions associated with holding arms crossed causing significant pain similar to restless leg syndrome. Affected persons may notice trembling in the diaphragm while breathing, or the need to place hands in pockets, under legs while sitting or under pillows while sleeping to keep them still and to reduce pain. Trembling in the jaw may be felt and heard while lying down, and the constant movement to avoid pain may result in the grinding and wearing down of teeth, or symptoms similar to TMD. The voice may crack frequently or become harsh, triggering frequent throat clearing. Swallowing can become difficult and accompanied by painful cramping.

Electrical sensors (EMG) inserted into affected muscle groups, while painful, can provide a definitive diagnosis by showing pulsating nerve signals being transmitted to the muscles even when they are at rest. The brain appears to signal portions of fibers within the affected muscle groups at a firing speed of about 10 Hz causing them to pulsate, tremble and contort. When called upon to perform an intentional activity, the muscles fatigue very quickly and some portions of the muscle groups do not respond (causing

weakness) while other portions over-respond or become rigid (causing micro-tears under load). The symptoms worsen significantly with use, especially in the case of focal dystonia, and a "mirror effect" is often observed in other body parts: use of the right hand may cause pain and cramping in that hand as well as in the other hand and legs that were not being used. Stress, anxiety, lack of sleep, sustained use and cold temperatures can worsen symptoms.

Direct symptoms may be accompanied by secondary effects of the continuous muscle and brain activity, including disturbed sleep patterns, exhaustion, mood swings, mental stress, difficulty concentrating, blurred vision, digestive problems and short temper. People with dystonia may also become depressed and find great difficulty adapting their activities and livelihood to a progressing disability. Side effects from treatment and medications can also present challenges in normal activities.

In some cases, symptoms may progress and then plateau for years, or stop progressing entirely. The progression may be delayed by treatment or adaptive lifestyle changes, while forced continued use may make symptoms progress more rapidly. In others, the symptoms may progress to total disability, making some of the more risky forms of treatment worth considering

[edit] Treatment

Although dystonias may be induced by chemical exposure/ingestion, brain injury, or hereditary/genetic predisposition, the task-specific focal dystonias such as writer's cramp are a unique challenge to diagnose and treat. Some cases may respond to chemical injections - botulinum toxin (botox) is often cited, though it is not helpful in all cases.[8] Behavioral retraining attempts may include changing technique, switching hands, physical therapy, biofeedback, constraint-induced motion therapy, and others. Some writing instruments allow variations of pressure application for use. None of these are effective in all cases, however.

opamine-responsive dystonia (DRD), also known as hereditary progressive dystonia with diurnal fluctuation, Segawa's disease, or Segawa's dystonia, is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years (variable start age).

Characteristic symptoms are increased muscle tone (dystonia, such as clubfoot) and Parkinsonian features, typically absent in the morning or after rest but worsening during the day and with exertion. Children with DRD are often misdiagnosed as having cerebral palsy. The disorder responds well to treatment with levodopa

Symptoms

The disease typically starts in one limb, typically one leg. Progressive dystonia results in clubfoot and tiptoe walking. The symptoms can spread to all four limbs around age 18,

after which progression slows and eventually symptoms reach a plateau. There can be regression in developmental milestones (both motor and mental skills) and failure to thrive in the absence of treatment.

In addition, DRD is typically characterized by signs of parkinsonism that may be relatively subtle. Such signs may include slowness of movement (bradykinesia), tremors, stiffness and resistance to movement (rigidity), balance difficulties, and postural instability. Approximately 25 percent also have abnormally exaggerated reflex responses (hyperreflexia), particularly in the legs. These symptoms can result in a presentation that is similar in appearance to that of Parkinson's Disease.

Many patients experience improvement with sleep, are relatively free of symptoms in the morning, and develop increasingly severe symptoms as the day progresses (i.e., diurnal fluctuation). Accordingly, this disorder has sometimes been referred to as "progressive hereditary dystonia with diurnal fluctuations." Yet some DRD patients do not experience such diurnal fluctuations, causing many researchers to prefer other disease terms.

For example, in those with DRD, symptoms typically dramatically improve with low-dose administration of levodopa (L-dopa), an amino acid that is a biologic "forerunner" or precursor of the neurotransmitter dopamine. (Neurotransmitters are naturally produced chemicals that may transfer nerve impulses across the spaces between neurons, enabling nerve cells to communicate.) Low-dose L-dopa usually results in near-complete or total reversal of all associated symptoms for these patients. In addition, the effectiveness of such therapy is typically long term, without the complications that often occur for those with Parkinson's disease who undergo L-dopa treatment. Thus, most experts indicate that this disorder is most appropriately known as dopa-responsive dystonia (DRD).

In severe, early autosomal recessive forms of the disease, patients have been known to pass away during childhood, but in other cases survival past age 50 has been reported. Girls seem to be somewhat more commonly affected. The disease less commonly begins during puberty or after age 20, and very rarely, cases in older adults have been reported.

[edit] Genetics and disease mechanism

Autosomal dominant and autosomal recessive forms of the disease have been reported. Mutations in several genes have been shown to cause dopamine-responsive dystonia. The neurotransmitter dopamine is synthesised from tyrosine by the enzyme tyrosine hydroxylase, which uses tetrahydrobiopterin (BH4) as a cofactor. A mutation in the gene GCH1, which encodes the enzyme GTP cyclohydrolase I, disrupts the production of BH4, decreasing dopamine levels (hypodopaminergia). This results in autosomal-dominant DRD. Mutations in the genes for tyrosine hydroxylase and sepiapterin reductase result in autosomal-recessive forms of the disease. When the latter enzyme is affected, the condition tends to be more severe. The activity of dopaminergic neurons in the nigrostriatal pathway normally peaks during the morning and also decreases with age until after age 20, which explains why the symptoms worsen during the course of the day and with increasing age until the third decade of life.

[edit] Diagnosis

The diagnosis of DRD can be made from a typical history, a trial of dopamine medications, and genetic testing. Not all patients show mutations in the GCH1 gene, which makes genetic testing imperfect.

Sometimes a lumbar puncture is performed to measure concentrations of biopterin and neopterin, which can help determine the exact form of dopamine-responsive movement disorder: early onset parkinsonism (reduced biopterin and normal neopterin), GTP cyclohydrolase I deficiency (both decreased) and tyrosine hydroxylase deficiency (both normal).

In approximately half of cases, a phenylalanine loading test can be used to show decreased conversion from the amino acid phenylalanine to tyrosine. This process uses BH4 as a cofactor.

During a sleep study (polysomnography), decreased twitching may be noticed during REM sleep.

An MRI scan of the brain can be used to look for conditions that can mimic DRD (for example, metal deposition in the basal ganglia can indicate Wilson's disease or pantothenate kinase-associated neurodegeneration). Nuclear imaging of the brain using positron emission tomography (PET scan) shows a normal radiolabelled dopamine uptake in DRD, contrary to the decreased uptake in Parkinson's disease.

Other differential diagnoses include metabolic disorders (such as GM2 gangliosidosis, phenylketonuria, hypothyroidism, Leigh disease) primarily dystonic juvenile parkinsonism, autosomal recessive early onset parkinsonism with diurnal fluctuation, early onset idiopathic parkinsonism, focal dystonias, dystonia musculorum deformans and dyspeptic dystonia with hiatal hernia

Myoclonus (pronounced /ma ɪˈɒ klənəs/ ) is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief lapses of contraction. Contractions are called positive myoclonus; relaxations are called negative myoclonus. The most common time for people to encounter them is while falling asleep (hypnic jerk), but myoclonic jerks are also a sign of a number of neurological disorders. Hiccups are also a kind of myoclonic jerk specifically affecting the diaphragm. Also when a spasm is caused by another person it is known as a "provoked spasm". Shuddering attacks with babies also fall in this category.

Myoclonic jerks may occur alone or in sequence, in a pattern or without pattern. They may occur infrequently or many times each minute. Most often, myoclonus is one of several signs in a wide variety of nervous system disorders such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, Subacute sclerosing panencephalitis and

Creutzfeldt-Jakob disease (CJD), serotonin toxicity, and some forms of epilepsy. Some researchers indicate that jerks persistently may even cause early tremors.

In almost all instances in which myoclonus is caused by Central Nervous System (CNS) disease it is preceded by other symptoms; for instance, in CJD it is generally a late-stage clinical feature that appears after the patient has already started to exhibit gross neurological deficits.

Anatomically, myoclonus may originate from lesions of the cortex, subcortex or spinal cord. The presence of myoclonus above the foramen magnum effectively excludes spinal myoclonus, but further localisation relies on further investigation with electromyography (EMG) and electroencephalography (EEG).

ymptoms

Myoclonic seizures can be described as "jumps." They are caused by rapid contraction and relaxation of the muscles. People without epilepsy can suffer small but similar jerks in the form of hiccups or brief twitches. These are perfectly normal.

In someone with epilepsy, myoclonic seizures cause abnormal movements on both sides of the body at the same time. In reflex epilepsies, myoclonic seizures can be brought on by flashing lights or other environmental triggers (see photosensitive epilepsy).

Familiar examples of normal myoclonus include hiccups and hypnic jerks that some people experience while drifting off to sleep. Severe cases of pathologic myoclonus can distort movement and severely limit a person's ability to sleep, eat, talk, and walk. Myoclonic jerks commonly occur in individuals with epilepsy. The most common types of myoclonus include action, cortical reflex, essential, palatal, progressive myoclonus epilepsy, reticular reflex, sleep, and stimulus-sensitive.

[edit] Types

In juvenile myoclonic epilepsy, seizures usually involve the neck, shoulders, and upper arms. These seizures typically occur shortly after waking up. They normally begin between puberty and early adulthood. They can usually be controlled with medication, but it must be taken for life.

In rare cases, myoclonic seizures can be symptomatic of Lennox-Gastaut syndrome, beginning in early childhood and usually involving the face, neck, shoulders, and upper arms. In these cases, the seizures tend to be strong and difficult to control.

Progressive myoclonic epilepsy includes both myoclonic and tonic-clonic seizures. Treatment is not normally successful for any extended period of time.

Classifying the many different forms of myoclonus is difficult because the causes, effects, and responses to therapy vary widely. Listed below are the types most commonly described:

Action myoclonus is characterized by muscular jerking triggered or intensified by voluntary movement or even the intention to move. It may be made worse by attempts at precise, coordinated movements. Action myoclonus is the most disabling form of myoclonus and can affect the arms, legs, face, and even the voice. This type of myoclonus often is caused by brain damage that results from a lack of oxygen and blood flow to the brain when breathing or heartbeat is temporarily stopped.

Cortical reflex myoclonus is thought to be a type of epilepsy that originates in the cerebral cortex - the outer layer, or "gray matter," of the brain, responsible for much of the information processing that takes place in the brain. In this type of myoclonus, jerks usually involve only a few muscles in one part of the body, but jerks involving many muscles also may occur. Cortical reflex myoclonus can be intensified when patients attempt to move in a certain way or perceive a particular sensation.

Essential myoclonus occurs in the absence of epilepsy or other apparent abnormalities in the brain or nerves. It can occur randomly in people with no family history, but it also can appear among members of the same family, indicating that it sometimes may be an inherited disorder. Essential myoclonus tends to be stable without increasing in severity over time. Some scientists speculate that some forms of essential myoclonus may be a type of epilepsy with no known cause.

Palatal myoclonus is a regular, rhythmic contraction of one or both sides of the rear of the roof of the mouth, called the soft palate. These contractions may be accompanied by myoclonus in other muscles, including those in the face, tongue, throat, and diaphragm. The contractions are very rapid, occurring as often as 150 times a minute, and may persist during sleep. The condition usually appears in adults and can last indefinitely. People with palatal myoclonus usually regard it as a minor problem, although some occasionally complain of a "clicking" sound in the ear, a noise made as the muscles in the soft palate contract.

Progressive myoclonus epilepsy (PME) is a group of diseases characterized by myoclonus, epileptic seizures, and other serious symptoms such as trouble walking or speaking. These rare disorders often get worse over time and sometimes are fatal. Studies have identified at least three forms of PME. Lafora disease is inherited as an autosomal recessive disorder, meaning that the disease occurs only when a child inherits two copies of a defective gene, one from each parent. Lafora disease is characterized by myoclonus, epileptic seizures, and dementia (progressive loss of memory and other intellectual functions). A second group of PME diseases belonging to the class of cerebral storage diseases usually

involves myoclonus, visual problems, dementia, and dystonia (sustained muscle contractions that cause twisting movements or abnormal postures). Another group of PME disorders in the class of system degenerations often is accompanied by action myoclonus, seizures, and problems with balance and walking. Many of these PME diseases begin in childhood or adolescence.

Reticular reflex myoclonus is thought to be a type of generalized epilepsy that originates in the brainstem, the part of the brain that connects to the spinal cord and controls vital functions such as breathing and heartbeat. Myoclonic jerks usually affect the whole body, with muscles on both sides of the body affected simultaneously. In some people, myoclonic jerks occur in only a part of the body, such as the legs, with all the muscles in that part being involved in each jerk. Reticular reflex myoclonus can be triggered by either a voluntary movement or an external stimulus.

Spinal myoclonus is myoclonus originating in the spinal cord, including segmental and propriospinal myoclonus. The latter is usually due to a thoracic generator producing truncal flexion jerk. It is often stimulus-induced with a delay due to the slow conducting propriospinal nerve fibers. [1]

Stimulus-sensitive myoclonus is triggered by a variety of external events, including noise, movement, and light. Surprise may increase the sensitivity of the patient.

Sleep myoclonus occurs during the initial phases of sleep, especially at the moment of dropping off to sleep. Some forms appear to be stimulus-sensitive. Some persons with sleep myoclonus are rarely troubled by, or need treatment for, the condition. However, myoclonus may be a symptom in more complex and disturbing sleep disorders, such as restless legs syndrome, and may require treatment by a doctor.

[edit] Cause

Rarely does myoclonus indicate anything other than arbitrary muscle contraction. Myoclonus may develop in response to infection, head or spinal cord injury, stroke, brain tumors, kidney or liver failure, lipid storage disease, chemical or drug poisoning, as a side effect of certain drugs (such as tramadol [2] and quinolones), or other disorders.

Benign myoclonic movements are commonly seen during the induction of general anesthesia with intravenous medications such as etomidate and propofol. These are postulated to result from decreased inhibitory signaling from cranial neurons. Prolonged oxygen deprivation to the brain, hypoxia, may result in posthypoxic myoclonus.

Myoclonus can occur by itself, but most often it is one of several symptoms associated with a wide variety of nervous system disorders. For example, myoclonic jerking may develop in patients with multiple sclerosis, Parkinson's disease, Alzheimer's disease,

Opsoclonus Myoclonus, Creutzfeldt-Jakob disease, or lupus. Myoclonic jerks commonly occur in persons with epilepsy, a disorder in which the electrical activity in the brain becomes disordered leading to seizures. It is also found in MERRF (Myoclonic Epilepsy and Red Ragged Fibres), a rare mitochondrial encephalomyopathy.

Jerks of muscle groups, much of the body, or a series in rapid succession which results in the person jerking bolt upright from a more relaxed sitting position is sometimes seen in ambulatory patients being treated with high doses of morphine, hydromorphone and similar drugs, and is possibly a sign of high and/or rapidly increasing serum levels of these drugs. Myoclonic jerks also can be caused by some unrelated drugs such as anticholinergics. Opioids which have other neurotransmitter impacts such as tramadol, pethidine, &c. can also cause jerks, but unlike the above are not completely benign.

[edit] Pathophysiology

Although some cases of myoclonus are caused by an injury to the peripheral nerves, most myoclonus is caused by a disturbance of the central nervous system. Studies suggest that several locations in the brain are involved in myoclonus. One such location, for example, is in the brainstem close to structures that are responsible for the startle response, an automatic reaction to an unexpected stimulus involving rapid muscle contraction.

The specific mechanisms underlying myoclonus are not yet fully understood. Scientists believe that some types of stimulus-sensitive myoclonus may involve overexcitability of the parts of the brain that control movement. These parts are interconnected in a series of feedback loops called motor pathways. These pathways facilitate and modulate communication between the brain and muscles. Key elements of this communication are chemicals known as neurotransmitters, which carry messages from one nerve cell, or neuron, to another. Neurotransmitters are released by neurons and attach themselves to receptors on parts of neighboring cells. Some neurotransmitters may make the receiving cell more sensitive, while others tend to make the receiving cell less sensitive. Laboratory studies suggest that an imbalance between these chemicals may underlie myoclonus.

Some researchers speculate that abnormalities or deficiencies in the receptors for certain neurotransmitters may contribute to some forms of myoclonus. Receptors that appear to be related to myoclonus include those for two important inhibitory neurotransmitters: serotonin, which constricts blood vessels and brings on sleep, and gamma-aminobutyric acid (GABA), which helps the brain maintain muscle control. Other receptors with links to myoclonus include those for opiates, drugs that induce sleep, and for glycine, an inhibitory neurotransmitter that is important for the control of motor and sensory functions in the spinal cord. More research is needed to determine how these receptor abnormalities cause or contribute to myoclonus.

[edit] Treatment

Discontinuation of drugs suspected of causing myoclonus and treatment of metabolic derangements may resolve some cases of myoclonus.[3] When pharmacological treatment is indicated anticonvulsants are the main line of treatment. Paradoxical reactions to treatment are notable. Drugs which most people respond to may in other individuals worsen their symptoms. Sometimes this leads to the mistake of increasing the dose, rather than decreasing or stopping the drug.[4] Treatment of myoclonus focuses on medications that may help reduce symptoms. Drugs used include sodium valproate, clonazepam and some other anticonvulsants such as piracetam and levetiracetam.[3] Dosages of clonazepam usually are increased gradually until the patient improves or side effects become harmful. Drowsiness and loss of coordination are common side effects. The beneficial effects of clonazepam may diminish over time if the patient develops a tolerance to the drug.

Many of the drugs used for myoclonus, such as barbiturates, phenytoin and primidone, are also used to treat epilepsy. Barbiturates slow down the central nervous system and cause tranquilizing or antiseizure effects. Phenytoin and primidone are effective antiepileptics drugs, although phenytoin can cause liver failure or have other harmful long-term effects in patients with PME. Sodium valproate is an alternative therapy for myoclonus and can be used either alone or in combination with clonazepam. Although clonazepam and/or sodium valproate are effective in the majority of patients with myoclonus, some people have adverse reactions to these drugs.

Some studies have shown that doses of 5-hydroxytryptophan (5-HTP) leads to improvement in patients with some types of action myoclonus and PME. These differences in the effect of 5-HTP on patients with myoclonus have not yet been explained, but they may offer important clues to underlying abnormalities in serotonin receptors.

The complex origins of myoclonus may require the use of multiple drugs for effective treatment. Although some drugs have a limited effect when used individually, they may have a greater effect when used with drugs that act on different pathways or mechanisms in the brain. By combining several of these drugs, scientists hope to achieve greater control of myoclonic symptoms. Some drugs currently being studied in different combinations include clonazepam, sodium valproate, piracetam, and primidone. Hormonal therapy also may improve responses to antimyoclonic drugs in some people.

Alcohol taken before sleep seems to help in relieving the symptoms, but long-term use of alcohol is not recommended and it is not a cure.

[edit] Prognosis

Although myoclonus is not a life-threatening condition, it may result in serious, debilitating impairments. Action myoclonus, with its positive and negative myoclonus components, is generally considered the most serious. It varies from person to person as to whether it is life-long.

Restless legs syndrome (RLS), also known as Wittmaack-Ekbom's syndrome, is a condition that is characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can also affect the arms or torso, and even phantom limbs.[1] Moving the affected body part modulates the sensations, providing temporary relief.

RLS causes a sensation in the legs or arms that can most closely be compared to a burning, itching, or tickling sensation in the muscles. Some controversy surrounds the marketing of drug treatments for RLS. It is a "spectrum" disease with some people experiencing only a minor annoyance and others experiencing major issues.

Signs and symptoms

The sensations—and the need to move—may return immediately after ceasing movement or at a later time. RLS may start at any age, including early childhood, and is a progressive disease for a certain portion of those afflicted, although the symptoms have disappeared permanently in some sufferers.[citation needed]

"An urge to move, usually due to uncomfortable sensations that occur primarily in the legs, but occasionally in the arms or elsewhere."[2]

The sensations are unusual and unlike other common sensations, and those with RLS have a hard time describing them. People use words such as: uncomfortable, "antsy", electrical, creeping, painful, itching, pins and needles, pulling, creepy-crawly, ants inside the legs, numbness, and many others. It is sometimes described as feeling similar to a limb "falling asleep". While it may be impossible to describe the sensation to someone without RLS, other RLS sufferers can easily relate to the peculiar sensation. The sensation and the urge can occur in any body part; the most cited location is legs, followed by arms. Some people have little or no sensation, yet still have a strong urge to move.

"Motor restlessness, expressed as activity, that relieves the urge to move."[citation

needed]

Movement will usually bring immediate relief; however, this relief will often be only temporary and partial. Walking is most common; however, doing stretches, yoga, biking, or other physical activity may relieve the symptoms. Continuous, fast up-and-down movements of the leg, is often done to keep the sensations at bay without having to walk. Sometimes a specific type of movement will help a person more than another.

"Worsening of symptoms by relaxation."[citation needed]

Any type of inactivity involving sitting or lying down: reading a book, a plane ride, watching TV or a movie, or taking a nap can trigger the sensations and urge to move. This depends on several factors: the severity of the person’s RLS, the degree of restfulness, the duration of the inactivity, etc.

"Variability over the course of the day-night cycle, with symptoms worse in the evening and early in the night."[citation needed]

While some only experience RLS at bedtime and others experience it throughout the day and night, most sufferers experience the worst symptoms in the evening and the least in the morning.

[edit] NIH criteria

In 2003, a National Institutes of Health (NIH) consensus panel modified their criteria to include the following:

1. an urge to move the limbs with or without sensations2. improvement with activity3. worsening at rest4. worsening in the evening or night.[3]

RLS is either primary or secondary.

Primary RLS is considered idiopathic, or with no known cause. Primary RLS usually begins before approximately 40 to 45 years of age. In primary RLS, the onset is often slow. The RLS may disappear for months, or even years. It is often progressive and gets worse as the person ages. RLS in children is often misdiagnosed as growing pains.

Secondary RLS often has a sudden onset and may be daily from the very beginning. It often occurs after the age of 40, however it can occur earlier. It is most associated with specific medical conditions or the use of certain drugs (see below).

[edit] Causes

[edit] Disease mechanism

Most research on the disease mechanism of restless legs syndrome has focused on the dopamine and iron system.[4][5] These hypotheses are based on the observation that iron and levodopa can be used to treat RLS, levodopa being a medicine for treating hypodopaminergic (low dopamine) conditions, and also on findings from functional brain imaging (such as positron emission tomography and functional magnetic resonance imaging), autopsy series and animal experiments.[6] Differences in dopamine- and iron-related markers have also been demonstrated in the cerebrospinal fluid of individuals with RLS.[7] A connection between these two systems is demonstrated by the finding of low iron levels in the substantia nigra of RLS patients, although other areas may also be involved.[8]

[edit] Underlying disorders

The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50 µg/L[9]), which accounts for just over 20% of all cases of RLS. Other conditions associated with RLS include varicose vein or venous reflux, folate deficiency, magnesium deficiency, fibromyalgia, sleep apnea, uremia, diabetes, thyroid disease, peripheral neuropathy, Parkinson's disease and certain auto-immune disorders such as Sjögren's syndrome, celiac disease, and rheumatoid arthritis. RLS can also worsen in pregnancy.[10] In a recent study, RLS was detected in 36% of patients attending a phlebology (vein disease) clinic, compared to 18% in a control group.[11]

Certain medications may worsen RLS in those who already have it, or cause it secondarily. These include: some antiemetics (the dopaminergic ones), certain antihistamines (often in over-the-counter cold medications), many antidepressants (both older TCAs and newer SSRIs), antipsychotics, and certain anticonvulsants. Treatment of underlying conditions, or cessation of use of the offending drug, often eliminates the RLS. Restless legs syndrome can occur as a result of the benzodiazepine withdrawal syndrome when discontinuing benzodiazepine tranquillisers or sleeping pills. A sedative hypnotic with a short half life may also induce restless legs syndrome when the dose wears off as part of a rebound effect.[12]

Hypoglycemia has also been found to worsen RLS symptoms.[13] Opioid detoxification has also recently been associated with provocation of RLS-like symptoms during withdrawal.[14] For those affected, a reduction or elimination in the consumption of simple and refined carbohydrates or starches (for example, sugar, white flour, white rice and white potatoes) or some hard fats, such as those found in beef or biscuits, is recommended. Some doctors believe it is caused by irregular electrical impulses from the brain.[citation needed]

Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.[15]

Some experts believe RLS and periodic limb movement disorder are strongly associated with ADHD in some children. Dopamine appears to factor into both conditions. In addition, many types of medication for the treatment of both conditions affect dopamine levels in the brain.[16]

The cause vs. effect of certain conditions and behaviors that are observed in some patients (ex. carrying excess weight, lack of exercise, suffering from depression or other mental illnesses) does not appear to be well established. The loss of sleep due to RLS could be the cause of the conditions, or the medication used to treat a condition could be the cause of an individual's RLS.[17][18]

[edit] Genetics

More than 60% of cases of RLS are familial[19] and are inherited in an autosomal dominant fashion with variable penetrance.

No one knows the exact cause of RLS at present. Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra (study published in Neurology, 2003).[20] Iron is an essential cofactor for the formation of L-dopa, the precursor of dopamine.

Six genetic loci found by linkage are currently known and are listed below. Other than the first one in this list, the remainder of the linkage loci were discovered using an autosomal dominant model of inheritance.

1. The first genetic locus was discovered in one large French Canadian family and maps on chromosome 12q.[21][22] This locus was discovered, however, using an autosomal recessive inheritance model. Evidence for this locus was also found using a transmission disequilibrium test (TDT) in 12 Bavarian families.[23]

2. The second RLS locus maps to chromosome 14q and was discovered in one Italian family.[24] Evidence for this locus was found in one French Canadian family.[25] Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.[26]

3. This locus maps to chromosome 9p and was discovered in two unrelated American families.[27] Evidence for this locus was also found by the TDT in a large Bavarian family,[28] as well as in a German family, in which significant linkage to this locus was found.[29]

4. This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.[30]

5. This locus maps to chromosome 2p and was found in three related families from population isolate in Bolzano-Bozen.[31]

6. The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.[32]

Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.[33] Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated to RLS [34]

There is also some evidence that periodic limb movements in sleep (PLMS) are associated with BTBD9 on chromosome 6p21.2.[35]

[edit] Diagnosis

The diagnosis of RLS relies essentially on a good medical history and physical examination. Sleep registration in a laboratory (polysomnography) is not necessary for the diagnosis. Peripheral neuropathy, radiculopathy and leg cramps should be considered in the differential diagnosis; in these conditions, pain is often more pronounced than the urge to move. Akathisia, a side effect of several antipsychotics or antidepressants, is a more constant form of leg restlessness without discomfort. Doppler ultrasound evaluation

of the vascular system is essential in all cases to rule out venous disorders which is common etiology of RLS. A rare syndrome of painful legs and moving toes has been described, with no known cause.[36]

[edit] Prevention

Other than preventing the underlying causes, no method of preventing restless legs has been established or studied.

[edit] Treatment

Treatment of restless legs syndrome involves identifying the cause of symptoms when possible. Pharmacotherapy involves dopamine agonists which are first line drugs for daily restless legs syndrome; gabapentin and opioids can be used for treatment of resistant cases.[37] The dopamine agonists pergolide, pramipexole, ropinirole, and cabergoline are preferred over levodopa as levodopa has problems of commonly having a rebound effect.[38] An algorithm for treating primary RLS (i.e., RLS that is not the result of another medical condition) was created by leading researchers at the Mayo Clinic and is endorsed by the Restless Legs Syndrome Foundation. This document provides guidance to both the treating physician and the patient, and includes both nonpharmacological and pharmacological treatments.[39] Treatment of primary RLS should not be considered until possible precipitating medical conditions are ruled out, especially venous disorders. Drug therapy in RLS is not curative and is known to have side effects such as nausea, dizziness, hallucinations, orthostatic hypotension, and sudden sleep attacks during the daytime. In addition, it can be expensive (about $100–150 per month for life), and thus it needs to be considered with caution.[citation needed]

Secondary RLS has the potential for cure if the precipitating medical conditions, anaemia, venous disorder, etc., are managed effectively. In many instances the alleged secondary conditions might be the only conditions causing the RLS; these include iron deficiency, varicose veins, and thyroid problems. Karl Ekbom in his original thesis on RLS in 1945 had suspected venous disease in about 12.5% of the cases he studied. But due to the unavailability of Doppler ultrasound imaging technology (the diagnostic tool that detects the abnormal blood flow in the veins, "Venous Reflux", the pathological basis for varicose veins) at that time, Ekbom may have underestimated the role of venous disease. In uncontrolled prospective series, improvement of RLS was achieved in a high percentage of patients who had presented with a combination of RLS and venous disease and had sclerotherapy or other treatment for the correction of venous insufficiency.[40][41]

[edit] Stretching and shaking legs

Stretching the muscles in the legs can bring instant and permanent relief, lasting several days or longer. This does not work for everyone: sometimes relief is temporary, and discomfort can return within the span of a few seconds.[42][43]

[edit] Iron supplements

According to some guidelines[citation needed], all people with RLS should have their ferritin levels tested; ferritin levels should be at least 50 µg for those with RLS. Oral iron supplements, taken under a doctor's care, can increase ferritin levels. For some people, increasing ferritin will eliminate or reduce RLS symptoms. A ferritin level of 50 µg is not sufficient for some sufferers and increasing the level to 80 µg may greatly reduce symptoms. However, at least 40% of people will not notice any improvement. Treatment with IV iron is being tested at the US Mayo Clinic and Johns Hopkins Hospital. It is dangerous to take iron supplements without first having ferritin levels tested, as many people with RLS do not have low ferritin and taking iron when it is not called for can cause iron overload disorder, potentially a very dangerous condition.[44]

[edit] Pharmaceuticals

For those whose RLS disrupts or prevents sleep or regular daily activities, medication may be required. Many doctors currently use, and the Mayo Clinic algorithm includes,[39] medication from four categories:

1. Dopamine agonists such as ropinirole, pramipexole, carbidopa/levodopa or pergolide. Ropinirole (Requip) was first approved In 2005 by the US Food and Drug Administration (FDA) to treat moderate to severe Restless Legs Syndrome. The drug was first approved for Parkinson's disease in 1997. Pramipexole (Mirapex, Sifrol, Mirapexen in the EU) received a positive recommendation by the EU Scientific Committee in February 2006. The FDA approved Mirapex for sale in the US in 2006. Rotigotine (Neupro), which is delivered by a transdermal patch was approved by the FDA in May 2007 for early stage Parkinson's disease; it is not yet approved for RLS in the US. The Neupro patch has been withdrawn from the US market due to problems with the medication delivery system. Rotigotine (Neupro), was approved for sale in the EU in 2007 for not only advanced stage Parkinson's disease but also for RLS. There are some issues with the use of dopamine agonists. Dopamine agonists may cause augmentation. This is a medical condition where the drug itself causes symptoms to increase in severity and/or occur earlier in the day. Dopamine agonists may also cause rebound, when symptoms increase as the drug wears off. Also, a recent study indicated that dopamine agonists used in restless leg patients can lead to an increase in compulsive gambling.[45]

2. Opioids are sometimes used when restless legs syndrome occurs with neuropathic pain or when other treatments fail to provide relief.[46]

3. Benzodiazepines , such as diazepam, which often in addition to symptom relief assist in staying asleep and reducing awakenings from the movements

4. Anticonvulsants , such as carbamazepine, help people who experience the RLS sensations as painful.[47]

Recently, several major pharmaceutical companies are reported to be marketing drugs without an explicit approval for RLS, which are "off-label" applications for drugs

approved for other diseases. The Restless Legs Syndrome Foundation[48] received 44% of its $1.4 million in funding from these pharmaceutical groups[49]

Quinine is frequently used off label to treat RLS, but is not recommended by the FDA due to its risk of serious hematological side effects.[50]

[edit] Ropinirole vs. Pramipexole

A meta-analysis published November 2007 combined previous 6-12 week long placebo-controlled studies done for ropinirole and pramipexole to indirectly compare adverse reactions and efficacy. It found that while both drugs had the same efficacy, pramipexole had significantly lower incidences of nausea, vomiting and dizziness. This led the authors to conclude "differences in efficacy and tolerability favouring pramipexole over ropinirole can be observed."[51]

[edit] The nondrug musculoskeletal approach

The nondrug musculoskeletal approach has been developed by a small group of doctors working at the London College of Osteopathic Medicine, London, UK and appears to produce relief of symptoms in 80–90% of patients. A small pilot study carried out at the London College of Osteopathic Medicine, using a specific form of manipulation, showed successful relief of symptoms in more than 80% of sufferers.[52] This followed the empirical observation that a large proportion of RLS sufferers have a "somatic dysfunction" at the lowermost level of the lumbar spine, and that a specific type of gentle manipulation could relieve their symptoms. One study has shown that RLS patients have increased, rather than the normal decreased, spinal cord excitability during sleep[53] and this fits with the osteopathic concept of spinal facilitation postulated by Korr. Specific types of manipulation appear to reduce this excessive sensory input and relieve symptoms. This nondrug treatment approach is free of the side effects associated with many of the drug treatments outlined above.

[edit] Prognosis

RLS is generally a lifelong condition for which there is no cure. Symptoms may gradually worsen with age, though more slowly for those with the idiopathic form of RLS than for patients who also suffer from an associated medical condition. Nevertheless, current therapies can control the disorder, minimizing symptoms and increasing periods of restful sleep. In addition, some patients have remissions, periods in which symptoms decrease or disappear for days, weeks, or months, although symptoms usually eventually reappear. A diagnosis of RLS does not indicate the onset of another neurological disease.

[edit] Epidemiology

Claims about the prevalence of restless legs syndrome can be confusing because its severity and frequency varies enormously between individual sufferers. RLS affects an

estimated 7% to 10% of the general population in North America and Europe.[54][55][56] A minority of sufferers (around 2.7% of the population) experience daily or severe symptoms.[55] RLS is twice as common in women as in men,[57] and whites are more prone to RLS than African Americans.[54] RLS occurs in 3% of individuals from the Mediterranean or Middle Eastern region, and in 1-5% of those from the Far East, indicating that different genetic or environmental factors, including diet, may play a role in the prevalence of this syndrome.[54][58] With age, RLS becomes more common, and RLS diagnosed at an older age runs a more severe course.[59]

RLS is even more common in individuals with iron deficiency, pregnancy and end-stage renal disease.[60][61] Neurologic conditions linked to RLS include Parkinson disease, spinal cerebellar atrophy, spinal stenosis, lumbosacral radiculopathy and Charcot-Marie-Tooth disease type 2.[54] Approximately 80–90% of people with RLS also have periodic limb movement disorder (PLMD), which causes slow "jerks" or flexions of the affected body part. These occur during sleep (PLMS = periodic limb movement while sleeping) or while awake (PLMW—periodic limb movement while waking).

The National Sleep Foundation's 1998 Sleep in America poll showed that up to 25 percent of pregnant women developed RLS during the third trimester.[62]

[edit] History

Earlier studies were done by Thomas Willis (1622–1675) and by Theodor Wittmaack.[63] Another early description of the ailment and its symptoms were made by George Miller Beard (1839–1883).[63] In a 1945 publication titled 'Restless Legs', Swedish neurologist Karl-Axel Ekbom (1907–1977)[63] described the disease and presented eight cases used for his studies.[64]

[edit] Controversy

As with many diseases with diffuse symptoms, there is controversy among physicians as to whether RLS is a distinct syndrome. The U.S. National Institute of Neurological Disorders and Stroke publishes an information sheet[65] characterizing the syndrome but acknowledging it as a difficult diagnosis. Physicians consider it a real entity that has specific diagnostic criteria.[66]

However, RLS and delusional parasitosis are entirely different conditions that share part of the Wittmaack-Ekbom syndrome eponym, as both syndromes were described by the same person, Karl-Axel Ekbom.[63]

Many doctors express the view that the incidence of restless leg syndrome is exaggerated by manufacturers of drugs used to treat it.[67] Others believe it is an underrecognized and undertreated disorder.[54] Some of the controversy results from the fact that certain pharmaceutical companies used medical representatives (i.e., salespeople) to perform investigations into the treatment of RLS, even though those companies had no licensed

treatments for the condition. Further, GlaxoSmithKline ran advertisements that, while not promoting off-license use of their drug (ropinirole) for treatment of RLS, did link to the Eckbom Support Group website. That website contained statements advocating the use of ropinirole to treat RLS. The ABPI ruled against GSK in this case.