Restless legs and/or sleep related periodic limb movements

Sylvia Boesch, Sub Subramony, Mary G. Kearney and Louise Corben

6.3.1 Background

Restless legs and periodic limb movements during sleep are significantly more common in those with FRDA than in the general population: Restless legs syndrome (RLS) has been reported to affect 44.8% of adults with FRDA (14) compared to between 4% and 14% of the general population (15). Moreover, an international multi-center natural history study of people with FRDA found that sleep disturbance was reported by 59% (290/495) of adults and 45% (72/161) of children due to abnormal limb movements or leg cramps (14).

Types of abnormal limb movements

There are several types of abnormal limb movements:
a) Restless legs syndrome (RLS)
b) Periodic limb movements in sleep (PLMS)
c) Flexor spasms
d) Nocturnal leg cramps (NLCs)

RLS and PLMS are the most common types of abnormal limb movements in people with FRDA. It is important that the clinician makes an accurate diagnosis and does not confuse symptoms of RLS with flexor spasms or NLCs.

Restless legs syndrome

RLS is a sensory motor disorder, also known as Willis-Ekbom disorder (WED). It was first described in detail by Swedish neurologist Dr Karl Ekbom in the 1960s.

The symptoms of RLS are uncomfortable and unpleasant sensations in the legs, feet or arms associated with an urge to move them:

a) that are typified by relief of symptoms by moving the affected limb
b) occur during rest in the evening or at night
c) are associated with sleep disturbance or impairment
d) that cannot be explained by any other condition (e.g. arthritis, leg cramps, myalgias) (16).

RLS is a clinical diagnosis based on the above criteria. Given their multiple neurological and systemic issues, questions about symptoms of RLS may not be asked of people with FRDA such that RLS is currently underdiagnosed.

RLS is associated with sleep disturbance, a risk of anxiety or depression, and poorer overall health status. Polysomnography or actigraphy should be carried out in those with FRDA if there is suspicion of a sleep disorder.

Periodic limb movements in sleep

PLMS is repetitive, highly stereotyped limb movements that occur in non-rapid eye movement (non-REM) sleep. Typically, the periodic limb movements (PLMs) are characterized by extension of the big toe, often in combination with partial flexion of the ankle, the knee and sometimes the hip (16). PLMS is assessed using polysomnography, often done overnight in a sleep laboratory, or actigraphy, which uses an accelerometer in a wrist-worn device. Actigraphy has been validated to assess total sleep time and wakefulness after sleep onset (17). PLMs may also occur when the person is awake and they may be more intense.

If the number of PLMs is greater than 15 per hour in adults, or five per hour in a child over the entire night, it is considered pathological and may result in clinically disturbed sleep. PLMS may also cause daytime fatigue.

Note that periodic limb movement disorder (PLMD) is a separate condition and should not be diagnosed in conjunction with RLS. PLMS is seen in 80 to 90% of people with RLS but PLMS is not specific to RLS (18).

The relationship between PLMS and RLS is currently an active field of research (18).

Flexor spasms

Flexor spasms in people with specific disorders (other than FRDA) are typically associated with clinically evident spasticity and brisk reflexes. In FRDA they can occur in the absence of such signs because the peripheral neuropathy associated with FRDA will mask such upper motor neuron signs. Flexor spasms respond poorly to medication which makes them difficult to treat (See Chapter 3.4: Spasticity and Spasms)

Nocturnal leg cramps

NLCs cause a tight, knotted feeling in the legs that usually happens at night. NLCs are similar to spasms but usually last much longer, from several seconds to several minutes. If the cramp is severe, the affected muscle may be sore for days. NLCs are different from RLS and are present in 33% of the general population over 50 years of age.

6.3.2 Assessment

At their annual or biannual review, all individuals with FRDA should:
1) be asked about sleep disturbances and complete the Epworth sleepiness scale, a screening questionnaire for sleep disorders (https://epworthsleepinessscale.com/about-the-ess/)
2) be assessed for spasticity and spasms on physical examination.

6.3.3 Diagnosis and management

There is no evidence supporting specific management strategies for RLS or PLMS in individuals with FRDA. As such, the clinician should adopt general management guidelines for RLS and PLMS (19), with specific considerations for FRDA. In particular, it is critical that accurate diagnosis of RLS and PLMS guide management.

Diagnosis

● A diagnosis of RLS is based on patient history. However, the treating physician must be aware of the specific diagnostic criteria for RLS so they can ask the patient the correct questions. Sleep studies should be undertaken if there is any suspicion of a sleep disorder.
● A low serum ferritin, i.e. < 50 mcg/l may be associated with RLS (20).  Therefore, serum ferritin in conjunction with iron studies, hematological and c-reactive protein blood tests should be part of the initial assessment.
● If PLMS is suspected, polysomnography or actigraphy should be done for confirmation of the diagnosis.
● Flexor spasms can be diagnosed from a history taken from the patient or family/carer and can be confirmed by clinical examination, as described above.
● NLC are diagnosed based on an accurate history, bearing in mind they do not usually occur every night.

Treatment of RLS

As RLS may be caused or precipitated by medication, an initial review of the person’s current medication should be undertaken, specifically asking about selective serotonin reuptake inhibitors (SSRI), tricyclics, lithium and metoclopramide, as well as some hypnotic agents, before any treatment is recommended (21).

Regular physical activity, sleep hygiene, regular hours for going to bed, avoiding the use of electronic devices in bed and reducing or avoiding caffeine, smoking and alcohol should be recommended. A review of non-pharmacological treatments for RLS reported some evidence for clinically significant effects from exercise, acupuncture, pneumatic compression devices and near infrared light (21). Up to 65% of patients with RLS regularly use alternative approaches for symptom relief (21). We suggest that non-pharmacological therapy for RLS should be tried first, especially for milder cases, before proceeding to pharmacological therapy.

If iron levels are found to be low, iron supplements may be trialed (22). However, as mitochondrial iron overload can play a role in FRDA pathogenesis, patients who are given iron supplements should be followed up with frequent reassessment of their iron and ataxia status and discontinuation of iron if ferritin reaches acceptable levels.

If correctly diagnosed, RLS responds to pharmacological treatment. Gabapentin and pregabalin are currently the preferred pharmacological choice (19). L-dopa and the dopamine agonists pramipexole and ropinirole are only recommended for occasional use in RLS due to the high risk of augmentation, characterized by an increase in the severity of RLS. These drugs can cause RLS to come on earlier in the day and have a faster onset when at rest, cause symptoms to spread to the upper limbs and trunk, and are associated with a shorter duration of the effect of treatment. Therefore, the calcium channel blockers gabapentin and pregabalin are the preferred options.

Treatment of PLMS

PLMS may be a clinical symptom of RLS and should be treated if the individual has disabling symptoms. Dopaminergic drugs such as levodopa and dopamine agonists pramipexole and ropinirole are recommended. A positive response to these medications may help confirm the diagnosis.

Lay summary of clinical recommendations for restless legs syndrome and/or periodic limb movements in sleep in Friedreich ataxia

Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) are five times more common in those with Friedreich ataxia than in the general population.

Restless legs syndrome

The key symptoms of RLS are an overwhelming urge to move the legs, typically late in the day while resting, such as in bed before sleeping, that is often but not always associated with uncomfortable or unpleasant sensations in the legs. These symptoms can be relieved by moving the legs or walking. This can lead to disturbed sleep. The symptoms cannot be accounted for by other medical conditions such as leg swelling, muscle aches, arthritis or habitual foot tapping.

Periodic limb movements in sleep

PLMS are spontaneous, repeated, jerky movements, usually of the leg, which occur during sleep. They often interfere with sleep and cause fatigue and sleepiness during the day. The presence of PLMS is confirmed by doing a sleep recording called polysomnography. This is usually done in a sleep laboratory where the individual spends the night. More recently it has been done with an actigraphy, which uses an accelerometer in a device on the wrist. Both devices record muscle contraction in the lower leg while sleeping. PLMS are found in 4 out of 5 people with RLS.

Why these recommendations?
It is not known why individuals with Friedreich ataxia experience RLS and PLMS more than other people and there have not been specific guidelines to help people with Friedreich ataxia manage RLS or PLMS. Based on some research and our clinical experience, we recommend the following assessments and treatments for people with Friedreich ataxia and restless legs:
● The physician that cares for your Friedreich ataxia should explore symptoms of RLS during your visits.
● A healthy lifestyle, including reducing alcohol and smoking, regular physical activity, regular hours for going to bed, and avoiding caffeine and electronic devices before sleep may help with RLS.
● A full blood count (FBC) and serum ferritin in conjunction with iron studies and C reactive protein (CRP) should be taken since abnormal values of these chemicals may be seen in RLS and correcting them may relieve the symptoms of RLS.
● All your current medications to be checked, to see if the symptoms may be linked to a medication you are taking. Anti-depressants of the types known as selective serotonin reuptake inhibitors (SSRI) or tricyclics, lithium, the anti-sickness tablet metoclopramide and some sleeping tablets are known to cause RLS.
● Some medications may help RLS that interferes with sleep. Gabapentin and pregabalin are currently the preferred choice of medication. Oral iron should be used with caution and only started if serum ferritin is less than 50 mcg/ml. Dopaminergic drugs are not recommended for RLS – although they may help the symptoms at first, they may make the symptoms significantly worse in the long-term.

What does this mean for you as a person living with Friedreich ataxia or caring for someone living with Friedreich ataxia?
It might be important for you to speak with your Friedreich ataxia healthcare professional if you are experiencing difficulties sleeping or have unexplained daytime fatigue or sleepiness. A healthy lifestyle with good sleep hygiene is recommended for those with Friedreich ataxia to try to avoid RLS and/or PLMs.

Who is this recommendation specifically for?
People with Friedreich ataxia who are experiencing restless legs before going to bed, sleep difficulties or unexplained fatigue.

These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.