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 an important group of sleep diseases encountered commonly in clinical practice that requires thorough evaluation and treatment. Some of the conditions included are 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 have stereotypic behavior. 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 a sleep study, and its mere presence alone does not satisfy the diagnosis of PLMD if there are no appropriate clinical symptoms.

Etiology

Most periodic limb disorders are associated with a multitude of conditions affecting sleep. 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][10][3] The diagnosis of primary PLMD can only be made in patients with subjective sleep complaints with evidence of PLMS in the absence of other sleep disorders. 

The diagnosis of primary PLMD can only be made in patients with subjective sleep complaints with evidence of PLMS in the absence of other sleep disorders. Demonstration of transient arousals and short awakening by sleep EEG usually accompanies diagnosing periodic limb movement disorders. 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, as a result, PLMD.[3] 

Certain genes like MEIS1 and BTBD9 that have links with RLS may be causing an increased incidence of PLMS.[5]

Similarly, iron deficiency and decreased ferritin may aggravate 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 seems to vary by population. Estimates range from 4% to 11 % in adults and 5 to 8% in children.[7] A European study estimated the prevalence to be 3.9% in the general population.[8] In this study, patients were diagnosed with PLMD based on a telephone-based screening questionnaire without any PSG evidence. So, this might not accurately reflect the prevalence. Older age, female gender, shift work, stress, and caffeine intake were thought to be some 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 exist, 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 in individuals with PLMSI >15 than in those with PLMSI < or =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 is not clearly defined. Previous studies suspected cortical or subcortical involvement in patients with PLMS.[11] However, recent studies favor the spinal cord location as a movement generator due to the similarity clinically 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 could be an underlying factor in triggering 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 the interneural circuitry or possible peripheral influence at the spine, or any combination of these.[16]

Several risk factors for PLM independently predict an increase in PLMSI >15/hour.[17][18] They are as follows:

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

A study by Li et al. showed a relationship between low ferritin and greater PLMs in a general population of older adults, independent of genetic polymorphisms, which suggested that low iron stores play a role in the expression of these phenotypes. Furthermore, high PLMI patients may need to be checked 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 endocrine carbohydrate metabolism regulation can be considered casual or genetically related, but this requires further studies. Furthermore, PLMD was found in 13 of 41 diabetic patients (31%) with lower non-REM slow-wave sleep, lower sleep efficiency, and higher arousal and PLM indexes.[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). Transplanted 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 at their provider’s office complaining of daytime fatigue, sleepiness, and insomnia. Collateral history from bed partner, if present, will include kicking of legs at night. A subset of patients may complain of frequent awakenings and problems with sleep onset due to these movements.[22] Repeated stereotyped lower extremity movements occur that resemble the Babinski sign (extension of the big toe and flexion of the ankle, knees, and hip).[23] These movements could cause autonomic arousal, which causes a change in heart rate and blood pressure, or cortical arousal either 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 focus on evaluating upper airway obstruction but also look for other abnormalities like peripheral neuropathy, peripheral vascular disease, and varicose veins.[24] As 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 ICSD-3, the diagnostic criteria includes the presence of PLMS of more than 15 periodic limb movements per hour in adults and more than five periodic limb movements per hour in children causing sleep problems, which impacts daytime functioning in the absence of any other sleep, psychiatry, or medical illnesses. In studies with sleep complaints related to other medical conditions, a cut-off of 5 distinct events recorded per hour of sleep is considered pathologic PLMS.[7][25]

As per the American Academy of Sleep Medicine (AASM) scoring criteria, each LM (limb movement) is scored if there is an increase in anterior tibialis EMG activity of >8 microvolts above the EMG activity at rest, lasting for a duration of 0.5 to 10 seconds. If there are > 4 LMs, then they can be included as PLM series (PLMS) as long as they are 5 to 90 seconds apart.  

Once again, PLMD is a diagnosis of exclusion.

Recently, it has been recognized that PLMS can be caused by upper airway resistance syndrome or mild obstructive sleep apnea, and correction with CPAP improved symptoms. However, it is interesting to note that the masking of underlying PLMS in severe OSA worsens during treatment. Also, CPAP by itself can cause PLMS.

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] Although there are no studies to support 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 2004 guidelines from a study by Grewal et al. and may be an option in some patients.[30]

Due to a lack of evidence on the pharmacological treatment of PLMD, clinical judgment is crucial before choosing the 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 be initially 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 will include:

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

Less common sleep-related movement disorders must also merit consideration.[32] These include:

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

The clinical focus while evaluating any patient with sleep-related limb movements is to ask for symptoms of restless leg 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 like RLS show improvement when these underlying conditions are treated. Symptomatically, patients who receive treatment with dopamine agonists and other medications notice an improvement in the nocturnal sleep quality, sleep efficiency, and sleep stages even though there is no significant reduction in the PLM index in the sleep study.[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 will benefit from education and discussion of possible causes of periodic limb movement disorder. As primary PLMD is rare, investigations of other etiologies should take place. 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 is a common finding in a polysomnogram. Unfortunately, it is an underdiagnosed condition. Having understood the potential cardiovascular adverse effects and the benefits in quality of sleep with treatment, all interprofessional healthcare team members, including clinicians (MDs, DOs, NPs, PAs), nurses, and even 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 will 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 mean by which to accomplish this. [Level 5]