Etiology

In both periodic limb movements of sleep (PLMS) and PLMD, the etiology is unclear. Lesion, imaging, and laboratory studies show that a subcortical origin for PLMS may exist, with neuronal hyperexcitability potentially arising from unsynchronized spinal generators and diminished descending inhibition from brainstem nuclei.[7][18][19][20][21][22]​​​ Decreased dopaminergic transmission has also been proposed, particularly in PLMS associated with restless legs syndrome and in conjunction with low iron states.[23][24][25]​​​ PLMD may be associated with diabetes mellitus, spinal cord tumor, sleep apnea syndrome, narcolepsy, congestive heart failure, essential hypertension, spinal cord injury, syringomyelia, alcohol dependence, Parkinson disease, Tourette syndrome, uremia, or anemia. PLMD may also be related to the drugs including lithium, tricyclic antidepressants, and selective serotonin-reuptake inhibitors (SSRIs).

Pathophysiology

A subcortical origin for periodic limb movements of sleep (PLMS) is supported by the absence of cerebral electroencephalogram potentials at the onset of electromyography (EMG)-detected limb movements during polysomnography.[7][18][19][20][21][22]​ EMG analysis of PLMS suggests a pattern of propagation attributable to propriospinal pathways, with motor activity beginning in muscles such as the quadriceps femoris before spreading to other leg and axial muscles.[7][18][19][20][21][22]​ PLMS have been reported in patients distally to a complete spinal cord transection and are observed during the induction of spinal anesthesia.[20] These observations have led to suggestions that PLMS are generated within the spinal cord and arise from the activation of several unsynchronized central spinal cord generators.[20][22]​ It has also been suggested that PLMS may be modulated by descending supraspinal influences potentially arising from the brainstem reticular system.[7][18][19][20][21][22]​ This hypothesis has received some support from functional MRI studies implicating dopaminergic brainstem regions in PLMS.[25] Dopaminergic hypoactivity has been postulated as a mechanism for PLMS associated with restless legs syndrome, with a reduction in dopaminergic transmission potentially exacerbated by low iron levels.[23][24][25]​ The symptomatic benefit yielded by opiates has led to theories that PLMS may result from a disturbed balance of dopamine-opiate inputs to neurotransmitters mediating motor actions and pain perception.

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