Nightmares & Disorders
Restless legs syndrome: the urge that only stops when you move
It affects perhaps one in twenty adults, it is frequently dismissed as a habit, it has a well-established link to iron in the brain, and the standard treatment can make it dramatically worse over time.
Restless legs syndrome — also called Willis–Ekbom disease — is diagnosed on five clinical criteria, all of which must be present.
- An urge to move the legs, usually with an uncomfortable sensation. People describe it as crawling, creeping, pulling, fizzing, or simply as something that is not pain and demands movement.
- The urge begins or worsens during rest or inactivity.
- It is partially or wholly relieved by movement, for as long as the movement continues.
- It is worse in the evening or at night, a clear circadian pattern.
- It is not better explained by another condition — leg cramps, positional discomfort, arthritis, neuropathy.
Prevalence in European and North American populations is commonly estimated at 5 to 10 per cent, with perhaps 2 to 3 per cent affected severely enough to warrant treatment. It is roughly twice as common in women, and rises with age.
The iron connection
This is the most useful thing to know about the condition, and it is often missed.
Brain iron deficiency is central to the pathophysiology. Post-mortem studies, cerebrospinal fluid analysis and MRI all show reduced iron in the substantia nigra of people with restless legs, and iron is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis.
Critically, brain iron status can be low while blood haemoglobin is entirely normal. The relevant measure is ferritin, and the threshold used in restless legs is far higher than the laboratory's normal range: guidelines recommend iron supplementation where ferritin is below 75 µg/L, and many laboratories flag anything above 15 as normal.
A patient told their iron is fine may well have a ferritin of 30 and a treatable cause of their symptoms.
Ferritin and transferrin saturation, with the restless-legs threshold in mind rather than the standard reference range. Also check renal function — restless legs is very common in chronic kidney disease and in dialysis patients — B12 and folate, and thyroid function. And review the medication list, because several common drugs cause or worsen it.
Drugs that make it worse
Frequently the entire explanation.
- Antihistamines, particularly sedating ones — including those in over-the-counter sleep aids, which is a cruel irony.
- Antidepressants — most SSRIs and SNRIs, and mirtazapine especially. Bupropion is the usual exception and may even help.
- Antipsychotics and dopamine-blocking antiemetics such as metoclopramide and prochlorperazine.
- Alcohol, caffeine and nicotine.
Periodic limb movements
Roughly 80 per cent of people with restless legs also have periodic limb movements of sleep — repetitive, stereotyped leg movements every twenty to forty seconds during sleep. These frequently cause arousals the sleeper does not remember, and are often reported first by a bed partner.
The two are related but distinct. Periodic limb movements occur in many people without restless legs and are not automatically pathological.
Treatment, and the trap in it
Iron replacement where ferritin is low. Oral iron, ideally taken on alternate days with vitamin C for better absorption, or intravenous iron where oral is ineffective or not tolerated. This can be genuinely curative and should be the first step.
Alpha-2-delta ligands — gabapentin enacarbil, pregabalin, gabapentin — are now recommended as first-line pharmacological treatment in most current guidelines. They are effective, and crucially they do not cause augmentation.
Dopamine agonists — pramipexole, ropinirole, rotigotine — were first-line for years and have been substantially downgraded. They work impressively at first, which is exactly the problem.
Augmentation
The reason for that downgrade, and the single most important thing for a patient on these drugs to know.
Augmentation is a paradoxical worsening of restless legs caused by long-term dopamine agonist treatment. Symptoms begin earlier in the day, become more intense, spread to other body parts including the arms and trunk, and the interval between taking the drug and symptom relief shortens.
It is frequently mistaken for disease progression, which prompts a dose increase, which accelerates the augmentation. Rates rise with duration and with dose, and after years of treatment a substantial proportion of patients are affected.
Withdrawal is difficult — symptoms are often severe during the taper — and usually requires specialist support and a transition to an alpha-2-delta ligand.
Anyone started on a dopamine agonist for restless legs should be told about augmentation explicitly, kept on the lowest effective dose, and reviewed. Many are not.
Non-drug measures
Moderate regular exercise helps, though intense exercise close to bedtime can worsen symptoms. Regular sleep timing, since sleep deprivation worsens it. Pneumatic compression devices have some trial evidence. Massage, stretching, warm or cool baths help some people. Reducing caffeine, alcohol and nicotine.
In pregnancy — where restless legs is common, particularly in the third trimester, and usually resolves after delivery — iron status is the priority and most medications are avoided.
Why it is worth pursuing
Restless legs is a genuine and often severe cause of sleep-onset insomnia. Patients are frequently treated with sedatives for years, which do not address the mechanism, while a ferritin test and a review of their antihistamine would have.
