Dyskinesias (Paroxysmal)

Pathophysiology

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.