Continuing Education Activity

Sleep-related movement disorders are an important group of sleep diseases encountered commonly in clinical practice that requires thorough evaluation and treatment. Periodic limb movement disorder or PLM is also referred to as sleep-related myoclonus syndrome or nocturnal myoclonus syndrome. These movements of the legs or upper limbs during sleep are periodic and have stereotypic behavior. Movements include flexion of the hip and knee and, most commonly, dorsiflexion of the foot, with the big toe extended. It is a common finding in a sleep study, and its mere presence alone does not satisfy the diagnosis of PLMD if there are no appropriate clinical symptoms. This activity explains the pertinent facts regarding a common finding of PLMS (periodic limb movements of sleep) in polysomnograms and PLMD (periodic limb movement disorders) and highlights the role of the interprofessional team in the evaluation and management of this condition.

Objectives:

• Identify the etiology of periodic limb movement disorder.
• Summarize the appropriate evaluation of periodic limb movement disorder.
• Outline the management options available for periodic limb movement disorder.
• Describe how an interprofessional team may coordinate care in patients with periodic limb movement disorder to improve outcomes.

Introduction

Sleep-related movement disorders are a frequently encountered category of sleep disturbances in clinical practice and warrant careful evaluation and management. This group includes conditions such as restless leg syndrome (RLS), periodic limb movement disorder (PLMD), sleep-related leg cramps, and bruxism. Periodic limb movement disorder, or PLM, is also referred to as sleep-related myoclonus syndrome or nocturnal myoclonus syndrome. These movements of the legs or upper limbs during sleep are periodic and stereotypic. Movements include flexion of the hip and knee and, most commonly, dorsiflexion of the foot, with the big toe extended.[1] It is a common finding in sleep studies, and its presence alone does not support a diagnosis of PLMD in the absence of appropriate clinical symptoms.

Etiology

Most periodic limb disorders are associated with multiple sleep-related conditions. The etiology of primary cases of periodic limb movement disorder is unclear. Conditions associated with PLMS include restless leg syndrome in 80 to 90% of cases (seen during sleep study), obstructive sleep apnea, narcolepsy, REM behavioral disorder, uremia, spinal cord tumor, and ADHD.[1][3][10] The diagnosis of primary PLMD can be made only in patients with subjective sleep complaints and evidence of PLMS, in the absence of other sleep disorders. 

The diagnosis of primary PLMD can be made only in patients with subjective sleep complaints and evidence of PLMS, in the absence of other sleep disorders. Demonstration of transient arousals and brief awakenings on sleep EEG usually accompanies the diagnosis of periodic limb movement disorder. These awakenings result in sleep disruption.[2] Risk factors for PLM can be related to the conditions mentioned above. A family history of RLS may be a risk factor for PLMS and, consequently, PLMD.[3] Certain genes, such as MEIS1 and BTBD9, which are associated with RLS, may be contributing to the increased incidence of PLMS.[5] Similarly, iron deficiency and low ferritin levels may exacerbate PLMS.[4] Medications like dopamine blockers, SSRIs, and TCAs could also increase the risk of PLMS.[5][6]

Epidemiology

The prevalence of periodic limb movement disorders appears to vary across populations. Estimates range from 4% to 11% in adults and from 5% to 8% in children.[7] A European study estimated a prevalence of 3.9% in the general population.[8] In this study, patients were diagnosed with PLMD based solely on a telephone screening questionnaire, without any PSG evidence. So, this might not accurately reflect the prevalence. Older age, female sex, shift work, stress, and caffeine intake were considered potential risk factors in this study. Some studies have found a reduced prevalence of PLMS in individuals of the Black race than in the White race.[9] A study revealed racial differences in this PSG parameter, with African Americans having a lower prevalence of PLMSI >15 than Caucasians (4.3% vs 9.3%; chi2 = 4.5, P < 0.05). However, insomnia was significantly higher among individuals with PLMSI >15 than among those with PLMSI <= 15 (45% vs 25%; chi2 = 6.84, P < 0.01), regardless of race.[9]

Pathophysiology

Periodic limb movement disorder is rarely a primary disorder. It is mainly associated with restless leg syndrome, which may be primarily idiopathic or secondarily due to pregnancy or systemic disorders, particularly iron deficiency and chronic renal insufficiency.[10] The pathogenesis of PLMD remains poorly defined. Previous studies suspected cortical or subcortical involvement in patients with PLMS.[11] However, recent studies favor the spinal cord as the site of movement generation, given its clinical similarity to the spinal flexor withdrawal reflex.[12][13] The hyperexcitability of spinal flexor pathways, especially during NREM sleep, could link to increased limb movements in sleep. Dopamine deficiency may be an underlying factor in the activation of these pathways.[14]

In a recent study, the role of the iron-dopamine hypothesis as an etiopathogenetic hallmark in RLS and the efficacy of treatment modalities in milder to more severe forms supported the discussion on the prevalence of secondary RLS among comorbid conditions like end-stage renal disease, idiopathic pulmonary fibrosis, attention-deficit/hyperactivity disorder, and irritable bowel syndrome. Currently, RLS treatment utilizes only symptomatic agents since a disease-modifying therapy is not yet evident.[15] A study by Rijsman et al suggests that in patients with PLMD, there is spinal-level inhibition. They suspect the following mechanisms: altered function in the descending spinal tracts, changes in interneural circuitry, peripheral influences at the spine, or any combination of these.[16]

Several risk factors for PLM independently predict an increase in PLMSI >15/hour, including the following:

• Age
• Male gender
• Restless leg syndrome
• Physical inactivity
• Current smoking
• Obesity
• Diabetes
• Antidepressant use
• Low magnesium
• Specific BTBD9, TOX3, and MEIS1 SNP distribution [17][18]

A study by Li et al reported an association between low ferritin and greater PLMs in a general population of older adults, independent of genetic polymorphisms, suggesting that low iron stores contribute to the expression of these phenotypes. Furthermore, patients with high PLMI may require evaluation for iron deficiency.[19] Since RLS and PLMDs are genetically related, there were studies among diabetic patients identifying them as potential hallmarks of these autonomic disorders. The relationship between PLMD-related sleep fragmentation and regulation of endocrine carbohydrate metabolism is likely causal or genetically related, but this requires further study. Furthermore, PLMD was observed in 13 of 41 diabetic patients (31%), who had lower non-REM slow-wave sleep, lower sleep efficiency, and higher arousal and PLM indices.[20]

Another study determined the prevalence of PLMS among transplanted and waiting-list haemodialysed patients through polysomnography. PLMS was observed in 27% of the transplanted and 42% of the waiting-list group (P = 0.094); the proportion of severe disease was twice as high in waiting-list versus transplanted patients (32 versus 16%, P = 0.024). Transplant patients had a higher risk of stroke. Meanwhile, both transplanted and wait-listed patients have a higher 10-year coronary heart disease risk.[21]

History and Physical

Patients with PLM may present to their provider’s office with daytime fatigue, sleepiness, and insomnia. Collateral history from bed partner, if present, includes kicking of legs at night. A subset of patients may report frequent awakenings and sleep-onset difficulties due to these movements.[22] Repeated stereotyped lower-extremity movements resembling the Babinski sign (extension of the big toe and flexion of the ankle, knee, and hip) occur.[23] These movements could elicit autonomic arousal, resulting in changes in heart rate and blood pressure, or cortical arousal, occurring before or after the PLMS. The clinician should query about symptoms of RLS and other sleep disorders like sleep apnea, narcolepsy, insomnia, and parasomnia, as the presence of these would rule out the possibility of PLMD.

The physical and neurological exams are normal in most cases of primary or idiopathic PLM. In other instances, anemia presenting as pallor, high BMI in obesity, and possible peripheral neuropathies from diabetes could be present. The examination should not only evaluate for upper airway obstruction but also assess for other abnormalities, such as peripheral neuropathy, peripheral vascular disease, and varicose veins.[24] These can also present as increased limb movements and leg discomfort in sleep.

Evaluation

The polysomnogram serves as an important diagnostic tool for PLMD. According to the ICSD-3, the diagnostic criteria include the presence of PLMS of more than 15 periodic limb movements per hour in adults and more than 5 periodic limb movements per hour in children, causing sleep problems that impair daytime functioning in the absence of any other sleep, psychiatric, or medical illnesses. In studies of sleep complaints associated with other medical conditions, a cutoff of 5 distinct events per hour of sleep is considered pathologic PLMS.[7][25]

According to the American Academy of Sleep Medicine (AASM) scoring criteria, a limb movement is scored when there is an increase in anterior tibialis electromyographic (EMG) activity of greater than 8 microvolts above resting baseline, with a duration of 0.5 to 10 seconds. A sequence of more than 4 limb movements may be classified as a periodic limb movement series (PLMS) if the movements are separated by intervals of 5 to 90 seconds. PLMD is a diagnosis of exclusion.

Recent evidence indicates that PLMS may occur secondary to upper airway resistance syndrome or mild obstructive sleep apnea (OSA), with symptom improvement following treatment with continuous positive airway pressure (CPAP). Notably, treatment of severe OSA may unmask previously suppressed PLMS, resulting in an apparent worsening during therapy. Additionally, CPAP itself has been reported to induce PLMS in some patients.

Treatment / Management

As most PLM is associated with RLS, dopaminergic medications such as pramipexole, ropinirole, rotigotine, and other drugs like gabapentin, pregabalin may also cause a reduction in periodic limb movements in patients with PLMD.[26] There are no studies supporting this treatment in patients with PLMD.

Based on a few small trials, researchers have tried some medications in patients with PLMD, including clonazepam, melatonin, valproate, and selegiline. Their effects on PLMS and other sleep indices appear below.

• Clonazepam 1 mg at bedtime: Improves sleep efficiency, sleep quality, and PLMS during wakefulness and REM sleep, but no reduction in PLM index.[27]
• Melatonin 3 mg 30 minutes before bedtime: Improves PLM and PLM arousal indices.[28]
• Valproate 125 to 600 mg at bedtime: Causes a non-significant reduction in PLM and PLM arousal indices. It improves sleep efficiency and the first and third sleep stages.[29]
• Selegiline was mentioned in the 2004 guidelines, based on a study by Grewal et al, and may be an option for some patients.[30]

Given the lack of evidence on the pharmacological treatment of PLMD, clinical judgment is crucial when selecting an appropriate therapy. Physicians should also be cautious in avoiding certain antidepressants like mirtazapine, venlafaxine, sertraline, fluoxetine, and amitriptyline, as they may aggravate periodic limb movements. Bupropion is the preferred medication in treating patients with concomitant depression. Other antidepressants like trazodone, nefazodone, and doxepin do not worsen PLMS.[31] In children, iron deficiency is a frequent finding in patients with RLS/PLMD. The primary focus should initially be on treating underlying iron deficiency anemia. Not much data is available on using dopamine agonists in children with RLS/PLMD.

Differential Diagnosis

Differential diagnosis of PLMS includes:

• Restless leg syndrome
• Peripheral neuropathy
• REM behavioral disorder
• Uremia

Less common sleep-related movement disorders must also merit consideration, including:

• Excessive fragmentary myoclonus (EFM)
• Sleep-related leg cramps, bruxism
• Rhythmic foot movements (RFM)
• Hypnagogic foot tremors (HFT)
• Alternating leg muscle activation (ALMA) [32] 

The clinical focus when evaluating any patient with sleep-related limb movements is to inquire about symptoms of restless legs syndrome. Then consider other common sleep disorders potentially associated with PLMS, like narcolepsy, OSA, REM behavioral disorder, and uremia. If any of these are present, then the diagnosis of PLMD cannot be made.

Prognosis

Patients whose PLM is secondary to underlying conditions such as RLS show improvement when these conditions are treated. Symptomatically, patients receiving dopamine agonists and other medications report improved nocturnal sleep quality, sleep efficiency, and sleep stages, even though the PLM index does not change significantly on sleep studies.[26]

Complications

Studies have shown abnormal blood pressure response and hypertension in patients with movement disorders in sleep due to an imbalance between the sympathetic and parasympathetic nervous systems.[33] As a result of increased sympathetic activity, RLS and PLMD patients are at a higher risk of hypertension, stroke, and heart disease.[34]

Deterrence and Patient Education

Patients benefit from education and discussion of possible causes of periodic limb movement disorder. Because primary PLMD is rare, investigations of other etiologies should be conducted. Treatment of the underlying condition, including RLS and sleep apnea, is beneficial for long-term health. Improving sleep quality secondary to treatment may be an adjunct in lowering risk factors for stroke, heart disease, and hypertension.

Enhancing Healthcare Team Outcomes

Periodic limb movements in sleep are a common finding on polysomnography. Unfortunately, it is an underdiagnosed condition. Having understood the potential cardiovascular adverse effects and the benefits in sleep quality with treatment, all interprofessional healthcare team members, including clinicians, nurses, and pharmacists, should be vigilant in identifying this condition and either diagnosing and treating these patients or referring them to clinical settings for a thorough diagnostic workup. This requires open communication channels between various healthcare disciplines, with each team member contributing their expertise. For example, pharmacists must ensure that the medication used for this condition does not interact with other medications the patient may already be taking, and can contact the nurse or clinician if they note any concerns. Nurses coordinate referrals, assist in evaluation, and counsel patients. Given the overall lack of understanding of this and other sleep disorders, it is crucial to get the patient where they need to be for proper diagnosis and management. This interprofessional paradigm is the optimal means by which to accomplish this.

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Disclosure: Valentina Joseph declares no relevant financial relationships with ineligible companies.

Disclosure: Shivaraj Nagalli declares no relevant financial relationships with ineligible companies.