Does iron deficiency disrupt the autonomic nervous system in a patient with Restless Legs Syndrome (RLS) and potential comorbid anxiety?

Iron Deficiency and Autonomic Nervous System Disruption in RLS

Iron deficiency does not directly disrupt the autonomic nervous system, but rather disrupts the dopaminergic system in the brain, which is the primary mechanism underlying RLS symptoms and may indirectly affect autonomic regulation through dopamine-mediated pathways. 1, 2

The Iron-Dopamine Connection in RLS Pathophysiology

The relationship between iron deficiency and RLS operates through a specific neurochemical mechanism rather than direct autonomic dysfunction:

• Brain iron deficiency, particularly in the substantia nigra, impairs dopamine transport and synthesis, which is the critical pathophysiological mechanism producing RLS symptoms 1, 2
• The substantia nigra requires adequate iron for proper dopaminergic neuron function, and reduced intracellular iron in this region compromises the dopamine system 1
• This brain iron insufficiency occurs even in patients without peripheral iron deficiency anemia, as demonstrated by cerebrospinal fluid studies, brain imaging, and autopsy findings 2, 3

Evidence for Brain-Specific Iron Deficiency

Multiple lines of evidence establish that RLS involves central nervous system iron insufficiency distinct from systemic iron deficiency:

• Cerebrospinal fluid and brain imaging studies independently demonstrate brain iron insufficiency in RLS patients without peripheral iron deficiency anemia 2
• Animal models (BXD40f mice) with isolated brain iron deficiency in the ventral midbrain (containing the substantia nigra) develop RLS-like behaviors during their active period, which worsen with dietary iron restriction and improve with dopaminergic treatment 4
• The brain iron deficiency pattern in RLS is region-specific, affecting the substantia nigra and ventral midbrain rather than causing global CNS iron depletion 2, 4

Clinical Implications for Comorbid Anxiety

While iron deficiency in RLS primarily affects the dopaminergic system rather than the autonomic nervous system directly, there are important considerations for patients with comorbid anxiety:

• Iron deficiency in the CNS can cause motor impairment and cognitive deficits, which may exacerbate anxiety symptoms 3
• The dopaminergic abnormalities caused by brain iron insufficiency may have downstream effects on mood regulation and anxiety, as dopamine pathways are interconnected with limbic and emotional processing systems 2
• Nonanemic iron deficiency (IDNA) in RLS patients is associated with severe tiredness and daytime sleepiness, which can worsen anxiety and quality of life 5

Screening and Treatment Thresholds

The approach to iron assessment in RLS differs from general population guidelines:

• Check morning fasting serum ferritin and transferrin saturation in all RLS patients, avoiding iron supplements for at least 24 hours before testing 6
• Iron supplementation is indicated when ferritin ≤75 ng/mL or transferrin saturation <20%, which are higher thresholds than used for general iron deficiency 1, 6
• Women are at much higher risk for nonanemic iron deficiency with RLS, with a relative risk of 5.51 compared to men 5

Treatment Efficacy

Iron therapy addresses the underlying pathophysiology rather than autonomic dysfunction:

• Iron therapy produces moderate improvement in RLS severity (mean difference -3.78 points on the IRLS scale) compared to placebo, with benefits mediated through restoration of dopaminergic function 7
• Intravenous iron formulations (particularly ferric carboxymaltose) are strongly recommended and may be more effective than oral iron, especially when ferritin is 75-100 ng/mL 1, 6
• The clinical response to iron treatment supports the hypothesis that brain iron deficiency biology directly produces RLS symptoms through dopaminergic mechanisms 4

Critical Pitfall to Avoid

Do not assume that RLS symptoms or comorbid anxiety are caused by autonomic nervous system dysfunction when iron deficiency is present—the primary mechanism is dopaminergic disruption in the substantia nigra, and correcting iron status should be the first intervention 1, 2. Treating anxiety with serotonergic medications (SSRIs) can actually worsen RLS symptoms, as these medications are known to exacerbate RLS 1.