How can restless‑legs syndrome present only on one side when its pathophysiology originates in the brain?

How RLS Can Present Unilaterally Despite Central Pathophysiology

While RLS pathophysiology involves central dopaminergic and iron-related mechanisms in the brain, unilateral presentation can occur because the disorder involves a complex network spanning from the brain through the spinal cord to peripheral nerves, and focal lesions at any level of this pathway can produce lateralized symptoms.

The Multi-Level Neuroanatomical Substrate

RLS is not purely a "brain disorder" but rather a somatosensory network disorder involving multiple levels of the nervous system 1:

• Central components: The substantia nigra (dopamine transport), thalamus, cerebellum, red nucleus, reticular formation, and somatosensory/motor cortex all show involvement 2
• Spinal cord integration: Abnormal spinal sensorimotor integration at the cord level contributes to symptom generation, with increased spinal excitability and decreased supraspinal inhibition 2
• Peripheral nervous system: Peripheral neuropathies can trigger RLS symptoms, demonstrating that peripheral pathology can produce the clinical syndrome 3, 2
• Diencephalospinal pathway: This descending pathway from brain to spinal cord may be critical, as evidenced by cases of RLS from focal spinal lesions 4

Evidence for Lesion-Related Unilateral RLS

Focal structural lesions can produce unilateral RLS, proving that lateralized pathology anywhere along the sensorimotor network can generate symptoms:

• A documented case of unilateral RLS occurred from hemorrhage of a thoracic spinal cord cavernoma at T9-T10, with the patient developing restlessness specifically in the legs ipsilateral to the lesion 4
• Stroke-related RLS involving the brainstem and lenticulostriate nuclei has been reported, often with lateralized symptoms 4
• Spinal cord lesions can produce RLS symptoms, and this association is likely underestimated in clinical practice 4, 1

Why Bilateral Presentation Is More Common

The standard diagnostic criteria describe RLS as affecting "the legs" (plural), indicating bilateral involvement is the typical pattern 5, 6:

• Primary (idiopathic) RLS involves diffuse dysfunction of central dopaminergic systems and iron metabolism affecting both hemispheres symmetrically 3, 2
• Even when asymmetric in severity, both legs are usually involved to some degree 6
• The bilateral pattern reflects the systemic nature of dopamine and iron dysfunction in most cases 3

Clinical Implications and Pitfalls

When encountering unilateral leg symptoms, perform a thorough neurological examination to identify focal pathology that distinguishes secondary from primary RLS 3:

• Check for radiculopathy or peripheral neuropathy with sensory testing and reflex examination 3, 6
• Consider spinal cord lesions if there are any upper motor neuron signs or sensory level 4
• Evaluate for vascular disease by palpating femoral, popliteal, dorsalis pedis, and posterior tibial pulses bilaterally 7
• Assess for venous stasis with examination for varicosities and edema, particularly with history of prolonged standing 7, 6

The physical examination is typically unremarkable in primary RLS, so any focal neurological findings should prompt imaging of the brain or spinal cord to identify structural lesions 3.

The Iron-Dopamine Model Explains Central Mechanisms

The predominant central pathophysiology involves 3, 2:

• Reduced intracellular iron in the substantia nigra impairing dopamine transport
• Dysfunction of the A11 diencephalospinal dopaminergic system that normally provides inhibitory control to the spinal cord
• Decreased supraspinal inhibition leading to increased spinal cord excitability

This central dysfunction can be modulated by focal lesions at any level, explaining how unilateral presentations occur when asymmetric pathology interrupts these pathways 4, 2.