05 November 2004
Paroxysmal dyskinesias are neurologic conditions characterized by sudden episodes of abnormal involuntary movements (hyperkinesias). These may include any combination of involuntary, rapid, randomly irregular jerky movements (chorea); relatively slow, writhing motions that appear to flow into one another (athetosis); increased muscle tone with repetitive, twisting, patterned movements and distorted posturing (dystonia); and uncontrollable flinging movements of an arm, a leg, or both (ballismus). The term paroxysmal indicates that the abnormal movements are sudden and unpredictable, with a relatively rapid return to normal motor function and behavior.
Paroxysmal dyskinesias are often classified into paroxysmal kinesigenic dyskinesia (PKD) and paroxysmal non-kinesigenic dyskinesia (PNKD), based upon precipitating factors that precede or trigger the episodes of abnormal, involuntary movement. In patients with PKD the episodes of hyperkinetic movements are provoked by sudden voluntary movement or unexpected stimuli (startle). In contrast, in those with non-kinesigenic dyskinesia, the attacks may occur spontaneously while at rest or out of a background of normal motor activity, but may be exacerbated by alcohol or caffeine consumption, stress, fatigue, or other factors. Other types of paroxysmal dyskinesias include episodes precipitated by prolonged exertion (paroxysmal exertion-induced dyskinesia) or sleep (paroxysmal hypnogenic dyskinesia).
Paroxysmal dyskinesias may also be further categorized according to the duration of the attacks. They may be described as "short-lasting" if episodes are less than or equal to 5 minutes or "long-lasting" if attacks are longer than 5 minutes. The paroxysmal dyskinesias may be familial, appear to occur randomly for unknown reasons (sporadically), or occur secondary to other underlying conditions (symptomatic).
Clinical Features and Classification
The primary finding associated with paroxysmal dyskinesia is sudden, transient attacks of chorea, athetosis, dystonia, ballismus, or any combination of these abnormal movements involving muscle groups of the arms, legs, trunk, face, and/or neck. These episodes may be relatively short- or long-lasting in duration and occur spontaneously or be brought on by sudden voluntary movement, stress, fatigue, caffeine, alcohol, heat, cold, prolonged exertion, sleep, or other factors. Following is a more in-depth description of these paroxysmal movement disorders, including some rare disease variants that have been described in the medical literature.
kinesigenic dyskinesia (PKD)
The transient attacks associated with PKD primarily affect muscles of the arms and legs; however, muscles of the face, neck, and/or trunk may also be involved. PKD episodes may affect muscle groups on one (unilateral) or both sides (bilateral) of the body, but even if bilateral they are usually asymmetrical. Involvement of facial or oromandibular muscles often results in transient facial grimacing, difficulties speaking (dysarthria), or even muteness; however, the episodes are not accompanied by altered consciousness. When leg and trunk muscles are affected, falls may occur, causing a risk of injury. PKD may interfere with walking or standing or conducting other activities of daily living (ADLs), potentially resulting in severe disability.
In addition to sudden movement, some episodes may also be provoked by unexpected stimuli (startle), yawning, talking, hyperventilation, the anticipation of movement, or light (photic) stimulation. Attacks may be worsened by certain factors, such as stress, cold, heat, or menstruation.
Most patients with PKD experience daily episodes. The frequency of attacks ranges from as few as 1 each month (or less) to as many as 100 each day. Before the onset of such episodes, some patients may experience unusual warning or "premonitory" sensations, such as prickling, tingling, or crawling (paresthesias); dizziness; or muscle tension. Such abnormal sensations usually involve the affected region. The frequency of PKD episodes usually decreases with age.
Generally, most patients with PKD have brief attacks lasting from seconds up to 5 minutes. However, some rare cases have been reported in which kinesigenic episodes may have a duration of more than 5 minutes up to hours. According to some reports, long-lasting PKD appears to be associated with an older age at symptom onset than that seen with short-lasting PKD; in addition, short-lasting episodes seem to occur more frequently than long-lasting attacks. It is also important to note that, in some patients with PKD, the length of attacks may change over time from short- to long-lasting or vice versa.
non-kinesigenic dyskinesia (PNKD)
Phenomenologically, PNKD is similar to PKD, except for the precipitating factors. This paroxysmal movement disorder was previously categorized as "paroxysmal dystonic choreoathetosis" (PDC). However, the term "paroxysmal non-kinesigenic dyskinesia" has since been recommended to more appropriately imply the larger spectrum of hyperkinetic movements potentially associated with the disease. As with PKD, PNKD attacks may be associated with any combination of various movement abnormalities, including chorea, athetosis, dystonic posturing, and ballismus. It is again important to emphasize that the episodes are not accompanied by an altered state of consciousness. Attacks may be so severe that they result in sudden falls or significantly interfere with walking, standing, or performing other activities of daily living (ADLs), potentially resulting in severe disability.
PNKD episodes may occur spontaneously without any specific "triggering" factors. However, episodes may be worsened by stress, anxiety, or excitement; fatigue; heat or cold; consumption of alcohol; intake of caffeine, such as in coffee, tea, or chocolate; fasting; or other factors.
The frequency of PNKD episodes is typically lower than that associated with PKD, ranging from approximately 2 to 3 per month up to about 20 per day; most patients with PKD experience daily attacks (up to 100 per day). In some patients, unusual "foreboding" sensations may occur prior to PNKD episodes. These may include prickling, crawling, or tingling sensations (paresthesias) or muscle tension in the affected region. As with PKD, PNKD attacks tend to decrease with age.
In contrast to usually brief episodes of PKD, the PNKD attacks last longer (from approximately 5 minutes up to about 4 hours or, sometimes, up to 2 days), although cases of PNKD have been reported in which non-kinesigenic episodes have a short-lasting duration of about 10 to 30 seconds (less than 5 minutes) . Thus, similar to PKD, PNKD is further classified based upon the duration of episodes into "short-lasting" (less than or equal to 5 minutes) or "long-lasting" (longer than 5 minutes). As with PKD, there have also been reports in which some patients with PNKD have experienced a change in the length of episodes from long- to short-lasting or vice versa. In addition, long-lasting PNKD appears to be associated with a younger age at symptom onset than that seen with short-lasting PNKD.
exertion-induced dyskinesia (PED)
In patients with idiopathic (familial or sporadic) PED, symptoms typically become apparent during childhood. In the only recorded case of secondary (symptomatic) PED, the age at onset was 29 years. In those with familial PED, females appear to be affected more frequently than males. However, in idiopathic sporadic PED, females and males are affected relatively equally.
PED is primarily characterized by sudden, transient, dystonic attacks, associated with involuntary, repetitive, twisting motions and distorted, often painful posturing. In some patients, attacks of dystonia may be accompanied by irregular jerky movements (chorea) and relatively slow, writhing movements that appear to flow into one another (athetosis). Such episodes are brought on by strenuous activity or prolonged exertion, such as running or walking for approximately 5 to 15 minutes. A few cases have also been reported in which PED attacks are provoked by passive movements of affected limbs. Episodes may be worsened by certain factors, including stress, cold, or menstruation. PED attacks primarily involve the legs or feet. However, muscles of the arms, face, neck, and/or trunk may sometimes be involved in those with short-lasting PED episodes (see below). Although muscle groups are often affected on both sides of the body (bilateral), only one side (unilateral) may be involved in some patients. Unlike PKD and PNKD, patients with PED usually do not experience any premonitory sensations prior to the onset of PED attacks.
Most patients with PED have about 1 to 5 episodes per month. However, some may experience up to 1 to 2 attacks daily. PED episodes usually have a duration ranging from about 5 to 30 minutes. Yet a few cases have been reported in which episodes were short-lasting, with a duration of seconds up to 2 minutes. In addition, in one family originally classified as having PNKD who had episodes precipitated by prolonged exertion, some affected members experienced both short- and long-lasting attacks: episodes lasted for a few seconds up to about a minute or as long as up to 2 days. Reports suggest that long-lasting PED episodes appear to be more common in younger individuals.
hypnogenic dyskinesia (PHD)
Idiopathic (familial or sporadic) PHD usually becomes apparent during childhood. Reports suggest that familial PHD typically has a younger age at symptom onset than sporadic disease. Based upon various reports, the age at onset may range from about 2 to 23 years in familial cases and approximately 3 to 47 years in idiopathic sporadic cases.
In some patients, PHD attacks may initially occur approximately 4 to 5 times each year. Over time, however, the frequency of episodes may increase up to 4 to 5 times nightly. The attacks are usually relatively brief, ranging from about 20 to 50 seconds or up to approximately 2 minutes. However, in some patients, episodes may have a longer duration of more than 5 minutes up to about 50 minutes.
In some instances, patients may experience nocturnal episodes as well as daytime kinesigenic or non-kinesigenic attacks. In addition, in some affected families (kindreds), different members may have different forms of paroxysmal dyskinesia.
The paroxysmal dyskinesias, including paroxysmal kinesigenic dyskinesia (PKD), non-kinesigenic dyskinesia (PNKD), exertion-induced dyskinesia (PED), and hypnogenic dyskinesia (PHD), are usually idiopathic (primary) conditions that occur for unknown reasons. Idiopathic PKD, PNKD, PED, or PHD may be familial, with autosomal dominant inheritance, or appear to occur randomly for unknown reasons (sporadically). The paroxysmal dyskinesias, however, may occur secondary to other underlying disorders, conditions, or other factors.
Genetic studies have mapped some but not all families of PKD to chromosome 16 (16p11.2-q11.2). This region overlaps with that of another autosomal dominant disorder known as familial infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome). The disorder is characterized by seizures during infancy and transient, non-kinesigenic episodes of involuntary movement. Some researchers suggest that these disorders may result from different mutations of the same gene or mutations of different genes within this chromosomal region. In other patients with idiopathic PKD, there is no apparent family history of the disease. Researchers suggest that such cases may be due to spontaneous (sporadic) genetic mutations that occurred for unknown reasons. In addition, some apparently sporadic cases may actually have been inherited; according to some investigators, this may be suggested by the fact that there are no apparent differences between familial and sporadic PKD regarding the frequency and duration of episodes, nature of the involuntary movement patterns (phenomenology), or response to treatment. Although many reports indicate that most cases of PKD are familial, other investigators suggest that sporadic (and secondary or symptomatic) disease may be more common than previously recognized.
Genetic analysis of a large multigenerational Italian family with PNKD with an autosomal dominant pattern of inheritance mapped the PNKD gene to chromosome 2 (2q33-q35). Although most reported cases of PNKD are familial, sporadic disease may actually be more common. In patients with idiopathic PNKD without a positive family history of the disease, PNKD may be caused by new genetic mutations that occurred for unknown reasons. There may be certain differences between familial and sporadic PNKD; sporadic cases tend to be characterized by a greater variability in the age at symptom onset, similar frequency of occurrence of the disease in males and females, short-lasting episodes that may have a duration of seconds, a higher frequency of episodes; and no premonitory sensations before the onset of the attacks. Some have suggested that sporadic PNKD may be underreported due to the challenges involved in establishing this diagnosis, including the apparent lack of family history and the need to differentiate PNKD from psychogenic movement disorders. A psychogenic disease is one in which symptoms have a mental or an emotional basis rather than an organic origin.
Paroxysmal exertion-induced dyskinesia (PED) and paroxysmal hypnogenic dyskinesia (PHD) are usually sporadic (idiopathic), although rare familial cases have been described. In addition to the paroxysmal dyskinesias, there has been an intense interest in the genetics of episodic ataxias, another group of disorders characterized by intermittent motor dysfunction (table).
PAROXYSMAL DYSKINESIAS: GENETICS
ICCA = infantile convulsions with paroxysmal dyskinesias
Etiology of Secondary Paroxysmal Dyskinesias
Symptomatic PKD is most commonly associated with head injury or multiple sclerosis (MS). MS is a progressive disease of the central nervous system characterized by loss of myelin, the fatty substance that forms a protective sheath around certain long nerve fibers. Myelin serves as an electrical insulator, thereby enabling the effective transmission of nerve signals. Associated symptoms may include lack of coordination, abnormal reflexes, muscle weakness, paresthesias, as well as visual and speech disturbances.
Symptomatic PKD may also be associated with idiopathic hypoparathyroidism, a condition characterized by decreased activity of the parathyroid glands, an unusually low level of calcium in the blood (hypocalcemia), and abnormal calcium deposits or calcifications in the basal ganglia. Symptomatic PKD may also occur in association with abnormalities of brain structure or function due to insufficient oxygen supply to tissues shortly before, during, or after birth (perinatal hypoxic encephalopathy). Cases are also described in the medical literature in which symptomatic PKD resulted from localized brain tissue loss or necrosis due to a temporary interruption of the blood supply to certain regions of the brain (cerebral infarction, e.g., thalamic, putamenal, or cortical infarct). Other underlying causes have also been implicated (e.g., diabetes mellitus, infantile hemiplegia).
Symptomatic PNKD is most frequently associated with MS or perinatal encephalopathy, but psychogenic etiology is also relatively common. Other causes include hypoparathyroidism, hyperthyroidism, and diabetes mellitus. Symptomatic PNKD may also occur in association with traumatic brain injury, inflammation of the brain (encephalitis), calcium deposits in the basal ganglia, lack of oxygen supply to brain tissues (anoxia), brief interruptions of blood supply to part of the brain (transient ischemic attacks), brain tumors, and or other underlying disorders or conditions. Symptomatic PNKD may also develop in individuals with acquired immunodeficiency syndrome (AIDS).
One case of secondary (symptomatic) paroxysmal exertion-induced dyskinesia (PED) has been reported following trauma as in neck, arm, and shoulder strain sustained during a car accident. In addition, 3 cases of symptomatic PHD have been described, 1 that resulted from head injury and 2 that were attributed to MS.
The basic underlying defects in the paroxysmal dyskinesias remain unknown. However, some investigators suggest that these movement disorders are "channelopathies," meaning that they result from abnormalities in the flow of certain electrically charged particles (ions, such as calcium, potassium, sodium) across cell membranes. This is supported by the observation that chromosome 2 (2q33-q35) contains genes known as ion channel genes. Ion channels permit the exchange of ions across cellular membranes, which is essential in various bodily processes. Mutations of certain ion channel genes have been identified in some individuals with other paroxysmal movement disorders, such as familial hyperkalemic or hypokalemic periodic paralysis, and episodic ataxias (see table).
The potential relationship of the paroxysmal dyskinesias to epilepsy remains unclear. Epilepsy refers to a group of neurologic conditions characterized by sudden, recurrent, uncontrolled electrical discharges from neurons of the cerebral cortex or the outer region of the brain. Due to a number of factors--including the sudden, unpredictable, transient nature of paroxysmal dyskinesia, its response to anticonvulsant medications, and the premonitory sensations often preceding episodes--some researchers have suggested that paroxysmal dyskinesia may be epileptic in nature. However, many investigators are skeptical of this interpretation due to the nature of the movement abnormalities and the fact that consciousness is unaltered and electroencephalography (EEG) brain wave readings are usually normal during episodes. In addition, epilepsy patients may temporarily be semiconscious and disoriented following certain seizure episodes (postictal state), findings that are not associated with paroxysmal dyskinesia. Yet some researchers have reported abnormal EEG patterns in a few PKD patients; in most such cases, however, these were considered "non-specific" findings that could not be attributed to epilepsy. Several reports suggest a possible "overlap" between paroxysmal dyskinesia and epilepsy, indicating that the conditions frequently occur in the same families (kindreds) and, in some cases, in the same patients.
Short-duration nocturnal episodes associated with paroxysmal hypnogenic dyskinesia (PHD) have also been considered a manifestation of epilepsy. As with PKD, such attacks respond effectively to anticonvulsant medications. Although EEG findings are usually normal during PHD episodes, the results of such studies in others have provided evidence supporting a relationship between PHD and seizures that arise from a certain region of the cerebral cortex (i.e., frontal lobe epilepsy).
Some investigators have suggested that dysfunction of the basal ganglia may play a role in paroxysmal dyskinesias. Abnormal metabolism within the basal ganglia has been demonstrated in some patients during a specialized imaging test, known as positron emission tomography (PET) or single photon emission computed tomography (SPECT). In addition, some patients have responded to therapy with levodopa (L-dopa), a precursor of the neurotransmitter dopamine, or tetrabenazine, a monoamine-depleting agent, potentially suggesting abnormalities in the dopamine neurotransmitter system in certain paroxysmal dyskinesias.
In animal studies of paroxysmal non-kinesigenic dystonia, medications that increased activity of the inhibitory neurotransmitter gamma-aminobutyric acid (i.e., GABAergic neurotransmission) reduced the severity and frequency of episodes. Such medications include the anticonvulsants phenobarbital and valproic acid and the benzodiazepine diazepam. In contrast, anticonvulsant agents that had no effect on GABAergic neurotransmission, such as carbamazepine and phenytoin, also had no effect on the paroxysmal non-kinesigenic dystonia. In addition, in clinical observations, patients with PKD respond effectively to anticonvulsant therapy, whereas only some with PNKD benefit from certain anticonvulsants (e.g., valproic acid or phenobarbital). (For further information, please see the section entitled "Treatment.") According to researchers, these and other observations suggest that different underlying mechanisms may be responsible for PKD and PNKD (as well as PED and PHD). Yet, overlapping clinical features among the different paroxysmal dyskinesias--as well as the occurrence of more than one form in some individuals and families--suggests that there may be a common mechanism in such disorders. Therefore, further research is required to learn more about the underlying cause or causes of this group of disorders.
The frequency of paroxysmal kinesigenic dyskinesia (PKD) and paroxysmal non-kinesigenic dyskinesia (PNKD) in the general population remains unclear, although both are thought to be rare disorders. It may be difficult to determine their true frequency since the disorders may remain undiagnosed or underreported. Some reports suggest that familial PKD may be more common in individuals of Japanese or Chinese ancestry than in other populations
A diagnosis of paroxysmal kinesigenic, non-kinesigenic, exertion-induced, or hypnogenic dyskinesia is based upon a thorough clinical evaluation including a complete physical and neurologic assessment; evaluation of characteristic symptoms with assessment of episode duration, frequency, and "trigger factors" or precipitants; and a careful patient and family history.
There is no definitive diagnostic test for these disorders. Certain blood tests, other laboratory studies, or neuroimaging or neurophysiologic studies may be conducted to eliminate similar disorders and to confirm or rule out underlying conditions that may result in secondary (symptomatic) paroxysmal dyskinesia. Such neuroimaging or neurophysiologic studies may include computerized tomography (CT) scanning or magnetic resonance imaging (MRI) to create detailed, cross-sectional images of certain bodily tissues and organs; electroencephalography (EEG) to detect or rule out potential seizure activity; or other techniques, such as specialized sleep studies (e.g., polysomnograms) in those with suspected paroxysmal hypnogenic dyskinesia to help evaluate the occurrence of nocturnal episodes of involuntary movement. However, experts indicate that neuroimaging studies (e.g., CT or MRI) typically are not helpful in those with idiopathic (familial or sporadic) paroxysmal dyskinesia.
The differential diagnosis of idiopathic paroxysmal kinesigenic dyskinesia (PKD) includes repeated seizures or epilepsy and hyperexplexia, also known as startle disease. Patients with hyperexplexia have an exaggerated startle response to unexpected stimuli. These heightened responses may cause stiffening and falling without loss of consciousness. Tetany, associated with hypocalcemia; may rarely mimic paroxysmal dyskinesias. It is characterized by muscular twitching and cramping; spasms at the wrist and ankle joints; spasmodic closure of the larynx, with an associated, high-pitched sound upon inhalation (stridor), and abnormal involuntary movements resembling chorea. The diagnosis of idiopathic, particularly sporadic, paroxysmal non-kinesigenic dyskinesia (PNKD) may include measures to help differentiate the condition from movement disorders in which symptoms have an emotional rather than an organic origin (psychogenic disease).
The differential diagnosis of paroxysmal hypnogenic dyskinesia should also include various forms of epilepsy. However, EEG findings may provide evidence of seizure activity arising from a specific region of the cerebral cortex.
Some authors suggest that the precipitating factor preceding episodes of paroxysmal dyskinesia is the most significant component in determining the course of the disease, the underlying disease mechanism (see "Pathophysiology"), and response to treatment. The duration of episodes also appears to have some effect on the disease course and treatment response.
kinesigenic dyskinesia (PKD)
Symptomatic PKD, such as that associated with multiple sclerosis (MS) or head injury, may also be relieved by anticonvulsant drug therapy, possibly in combination with other appropriate agents (e.g., acetazolamide). Depending upon the nature of the underlying or primary condition, other therapies may be required to help control kinesigenic episodes. For example, in patients with symptomatic PKD in association with decreased activity of the parathyroid glands (hypoparathyroidism) and abnormal calcium deposits (calcifications) within the basal ganglia, administration of calciferol (ergocalciferol), a vitamin D analog, may help to alleviate PKD episodes.
non-kinesigenic dyskinesia (PNKD)
In addition, in some patients with symptomatic PNKD, administration of appropriate therapies to manage an underlying condition, such as certain endocrine disorders (e.g., diabetes or idiopathic hypoparathyroidism), may alleviate non-kinesigenic episodes.
exertion-induced dyskinesia (PED)
hypnogenic dyskinesia (PHD)
Most patients with short-lasting PHD episodes benefit from carbamazepine. In some cases, other anticonvulsants may also be effective, such as phenytoin (Dilantin®) or combination therapy with phenytoin and phenobarbital. In contrast, according to reports in the medical literature, those patients with long-lasting nocturnal attacks did not respond to anticonvulsant therapy, nor were administration of benzodiazepines or certain antipsychotic agents (phenothiazines) effective. However, a patient with long-lasting PHD secondary to head trauma had an effective response to therapy with the carbonic anhydrase inhibitor acetazolamide.
In addition to medical therapy, surgical interventions such as chronic thalamic stimulation, are being explored as potential therapies in patients with medically intractable paroxysmal dyskinesias.
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