Disorder
Description
Urge to Move
Sensory Symptoms
Sleep Disruption
Circadian Pattern
Sleep-related disorders
• Periodic limb movements of sleep
Involuntary leg movements while asleep, at regular intervals before one enters REM sleep. People who suffer from PLMS can be unaware of their limb movements, as they do not always wake from them. Sleep disturbance and daytime sleepiness may be present. Diagnosis made by polysomnography. Positive response to dopaminergic therapy
No
No
Maybe
Yes
• Nocturnal myoclonus
Involuntary myoclonic twitch occurring once or twice while falling asleep. May cause sudden awakening for a moment
No
No
No
Yes
Neurological disorders
• Neuroleptic-induced akathisia
Appears like severe RLS but affects the entire body, often seen as entire body rocking. Less circadian pattern and less relief from movement. Associated with dopamine antagonists
Yes
Yes
Yes
Yes
• Hypotensive akathisia
Feeling of restlessness, brought on by sitting still, which may be localized in legs; should not occur while lying down but might be relieved by movement; occurs in patients with orthostatic hypotension
Yes
No
No
No
• Volitional movements, foot tapping, leg rocking
Occurs in subjects who fidget, especially when bored or anxious, but usually not associated with sensory symptoms, discomfort, or conscious urge to move. Symptoms do not bother the subject, usually lack a circadian pattern, and do not cause sleep disturbances
Yes
No
No
No
• Painful legs and moving toes
Predominant involvement of feet. Movement is truly involuntary, no circadian pattern. Usually a continuous slow writhing
Yes
No
No
No
• Isolated leg stereotype
Fast (>3 Hz) rhythmic plantar flexion/dorsiflexion movements oscillating around ankle, but sometimes involving other parts of the leg. Usually a tremor phenotype, but not considered a true tremor. It is easily suppressed and is almost always seen only while sitting. The condition is common, not considered pathologic, and may be an alerting activity
Yes
No
No
No
• Orthostatic tremor
Fine leg tremor manifest by a sense of poor balance while standing, but not while walking. Therefore, patients cannot stand still but need to walk. Unlike RLS, there are no symptoms while sitting or lying down and no circadian pattern
Yes
No
No
No
• Nocturnal cramps
Leg cramps that come on at night and are relieved with stretching or walking. Experienced as an unusually painful muscular contraction, often involving the calf muscles. Unlike RLS, sensations are sudden onset, short duration, usually palpable contractions
No
No
No
Yes
• Arthritis, lower limb pain
Discomfort centered mostly in joints, increased with movement
No
No
No
No
• Positional discomfort
Often comes on with prolonged sitting or lying in the same position, but usually relieved by a simple change in position
No
No
No
No
Vascular disorders
• Vascular claudication
Muscle pain often in form of ache, cramp, numbness or sense of fatigue, classically in the calf muscle, which occurs during exercise, such as walking, and is relieved by rest, often best in a lying position
No
Maybe
No
No
• Varicose veins
May have discomfort in legs, some relief with massage or inactivity
No
No
No
No
Pain disorders
• Myelopathy, radiculopathy
Sensory symptoms and pain in the legs, frequently one-sided, often radicular, with atrophic changes of musculature
No
Yes
Maybe
No
• Peripheral neuropathy
Sensory symptoms often in form of numbness, burning, and pain. Complete and persistent relief is not obtained during sustained movement
No
Yes
Maybe
No
• Isolated leg pain
Undiagnosed leg pain or ache in the muscle may be seen without other explanation. The examination and evaluation is normal. Often worse at night and may improve with movement but there is no true urge to move
No
No
Maybe
No
• Fibromyalgia
Multiple, alternating, varied complaints in muscle groups and joints; sometimes leg accentuated but mostly whole body affected. Frequent sleep disturbances, but no circadian pattern, no relief from movement
No
No
Yes
No
RLS may be a primary or a secondary condition. Secondary RLS is thought to be due to an underlying medical condition or in association with the use of certain drugs. The strongest evidence for drug-induced RLS has been shown in fluoxetine, escitalopram, levodopa, carbidopa, pergolide, levothyroxine, mianserin, mirtazapine, olanzapine, and tramadol [32]. Involvement of the dopaminergic system in RLS is supported by the great response of RLS to dopamine agonists [33]. Antidepressants, particularly serotonin-specific reuptake inhibitors (SSRI ) , such as fluoxetine inhibit the dopamine system and can evoke dopamine-dependent side effects and exacerbate RLS [34, 35]. In Mark’s case, RLS was induced by fluoxetine and resolved with removal of the agent. The antidepressant bupropion was particularly beneficial in this case, as it also inhibits dopamine reuptake and has shown to be effective in RLS without dopamine-like side effects, such as rebound or tolerance [36, 37].
RLS can influence sleep and daytime functioning. It is therefore important to avoid drugs that may provoke RLS although potential offending medications such as antidepressants should be withdrawn only after considering the patient’s overall status and in consultation with other health providers.
Pitfalls
RLS is frequently overlooked as a side effect of certain medications.
Common mimics in adolescents are positional discomfort, nocturnal cramps , nocturnal myoclonus , volitional movements, foot tapping, leg rocking, or arthritis.
Learning Points
Knowledge of medication side effects and interactions is critical to physicians and their patients.
Evaluation for possible medication side effects is important on every patient encounter.
Case 3
Christopher is a 15-year-old young man who was diagnosed with stage II chronic kidney disease (CKD ) in the setting of reflux nephropathy 2 years ago. He presents to the office with his parents with the complaints of difficulty sleeping and fatigue, and the concern that his renal function may be causing his symptoms. In the course of the conversation, he discloses leg pain and a tingling sensation in the evenings when lying in bed. His symptoms improve temporarily with movement. Following further inquiry, Christopher realizes that he has been having these symptoms for at least 1 year, but they have been increasingly bothersome for the past couple of weeks. He denies tobacco use, alcohol, or caffeine intake. He takes nephro vitamins on a daily basis. His detailed general and neurological physical examination has been normal. Results of his biochemical investigations showed further decline in his renal function to stage III CKD, but normal complete blood count, serum ferritin, transferrin saturation, thyroid function, vitamin B12, and folic acid levels. His clinical picture raised concern for RLS related to CKD. As agreed with Christopher and his parents, the decision was made to initiate a treatment trial with Gabapentin 100 mg at bedtime. On 2-weeks follow-up, Christopher reports notably reduced leg pain and tingling, as well as improved sleep and daytime energy.
Discussion
Sleep disorders are common in adolescents with CKD and frequently occur even before the need for renal replacement therapy. RLS is one of the most common sleep disorders in patients with CKD and has been reported to affect up to one-third of adolescents [38, 39]. The severity of CKD correlates with the severity of RLS symptoms: mild renal dysfunction has minimum or no impact on the development of RLS, while those with end-stage renal disease experience the most severe symptoms [40–42].
The exact etiology of RLS in patients with CKD is unknown. The importance of uremia as a cause of RLS has been shown on the one hand through improved symptoms in dialysis patients after successful renal transplantation, and on the other hand, by recurrence of symptoms in those with progressive renal dysfunction [43]. Additional risk factors include iron deficiency, anemia , peripheral neuropathy associated with uremia, and alterations in dopaminergic and opioid neuronal pathways within the central nervous system [44].
Non-pharmacologic therapies are the initial step in the treatment of RLS in adolescents. These focus on correction of contributing factors, such as appropriate bedtime habits, use of local comfort aids for leg discomfort, intake of a healthy and well-balanced diet, avoidance of caffeinated products, elimination of unnecessary medications, moderate regular exercise, including over the counter products and herbal products [45–49].
The decision to initiate pharmacologic therapy should be individualized, with the goals of therapy to reduce RLS symptoms, sleep disturbance, functional limitations, and to improve quality of life. Pharmacological therapies are usually reserved for cases of moderate to severe RLS with significant functional limitations and should be combined with non-pharmacological measures to achieve optimal results. Even though there are no FDA approved medications for the treatment of RLS in adolescents, the medical literature supports the careful use of certain medications [50–53]. Treatment should be initiated at the lowest dose possible, with slow symptom-based up-titration, while monitoring for adverse effects [31].
The first step usually consists of micronutrient supplementation, in particular iron and folic acid [54, 55]; however, ferritin levels are generally higher in individuals with impaired renal function due to their chronic inflammatory state [56]. It is therefore difficult to show a relation between ferritin levels and the presence of RLS in the CKD population, even though two-thirds of these patients have been shown to be iron deficient [39]. Even though Christopher’s ferritin levels were normal, iron therapy may have a beneficial effect, as clinical experience has shown response to iron replacement therapy in individuals with RLS in the setting of CKD.
Other pharmacologic agents that can be considered in the treatment of RLS include dopaminergic agents (e.g., carbidopa-levodopa), dopamine agonists (e.g., ropinirole, pramipexole), benzodiazepines (e.g., clonazepam), anticonvulsants (e.g., gabapentin), and others including clonidine [57–60]. Special attention is recommended when initiating pharmacologic therapies in adolescents with renal dysfunction. For example, Gabapentin’s renal excretion is proportional to the individual’s renal function; dose adjustment is recommended based on creatinine clearance, and supplemental dosing is needed after hemodialysis. Pramipexole is also cleared predominantly via renal excretion; utmost caution is recommended when used in individuals with renal impairment, and dose adjustment may be necessary. In contrast, ropinirole is extensively metabolized through the liver; dose adjustments are not required for individuals with CKD, neither are post-dialysis supplemental doses needed [33, 61–65]. Some of these agents will be removed with dialysis, which may result in worsening of RLS symptoms and will require post-dialysis supplemental dosing (Table 3.2).
Drug | Mechanism of action | Dosage | Metabolism | Excretion | Dose Adjustment in CKD | Dialyzable | Post-dialysis supplemental dosing | Adverse effects |
|---|---|---|---|---|---|---|---|---|
Clonidine | Central α2 adrenergic receptor agonist | 0.05–0.3 mg | Extensively hepatic to inactive metabolites; enterohepatic recirculation | Urine (40–60 % as unchanged drug) | Yes | No | No | Hypotension, bradycardia, dry mouth |
Clonazepam | GABA-A receptor agonist | 0.01 mg/kg | Extensively hepatic via glucuronide and sulfate conjugation | Urine (<2 % as unchanged drug); excreted metabolites | No (cautious use in CKD, metabolites may accumulate) | No | No | Daytime sedation, cognitive difficulties, antegrade amnesia |
Levodopa/Carbidopa | Metabolic precursor of dopamine | 25/100 mg (up to 3 tabs/day) | Peripheral tissue and CNS | Urine | No (contraindicated in uncompensated renal disease) | No | No | Hallucinations, confusion, orthostatic hypotension |
Pramipexole | Nonergot dopamine receptor agonist | 0.125–0.75 mg | Negligible (<10 %) | Urine (90 % as unchanged drug) | No (cautious use) | No | No | Headaches, hypotension, insomnia, daytime somnolence |
Ropinirole | Nonergot dopamine receptor agonist | 0.5–4 mg | Extensively hepatic via CYP1A2 to inactive metabolites | Urine (<10 % as unchanged drug, 60 % as metabolites) | No | No | No | Headaches, hypotension, insomnia, daytime somnolence |
Gabapentin | May potentiate neuronal GABA synthesis | 100–500 mg | Not metabolized | Urine (as unchanged drug); proportional to renal function
Related posts: Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Get Clinical Tree app for offline access
|
