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The impact of restless legs syndrome: a familial case study.

ABSTRACT

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move. RLS has a general population incidence of between 5% and 10% and a familial rate as high as 77%. This case study examines the pathophysiology, diagnosis, and treatment along with the presentation of RLS in two members of a family with near-identical onset and treatment. Cases of familial RLS may be best directed toward similar treatment regimens.

Keywords: case study, familial, restless legs syndrome, RLS

Overview

Restless legs syndrome (RLS) is a common neurological disorder affecting between 5% and 10% of the population, with a slightly higher predominance in women than men (Hening et al., 2004, Winkelmann & Ferini-Strambi, 2006). Current research implicates, but does not exclusively prove, that RLS is the result of disruption to the body's dopamine and opioid systems and points more strongly toward iron packaging and transport deep within the brain (Fulda & Wetter, 2008). RLS has a strong familial correlation with between 60% and 77% of patients reporting a family history of RLS (Hanson et al., 2004; Xiong et al., 2010). RLS is characterized by unpleasant sensations in the legs or elsewhere in the body and often described as "creepy-crawly" resulting in the urge to move (Whittom et al., 2007). The aforementioned sensations usually occur in the evening or during periods of rest and consequently have negative effects on sleep, mood, and quality of life (Tzonova et al., 2012).

RLS has been found to be a widely undiagnosed/ untreated condition with sleep-related symptoms, uncomfortable feelings in the legs, and pain reported as being the most troublesome by RLS sufferers (Hening et al., 2004). In a 2004 study of over 23,000 patients, 68.6% of people with RLS reported that it took over 30 minutes to achieve sleep with 60.1% reporting waking during sleep three or more times per night (Hening et al., 2004). Of those studied, the majority reported a decrease in energy during episodes of RLS, having a hard time relaxing or sitting still, difficulty with activities of daily living, and feelings of depression, and 49.7% reported that RLS was adversely affecting concentration (Hening et al., 2004).

Diagnosis

RLS can be classified as either primary (idiopathic) or secondary as the result of anemia, pregnancy, spinal trauma, or chronic kidney disease. There are currently no approved diagnostic tests used in the diagnosis of RLS. Patient history and questionnaire using the following criteria have been validated in the diagnosis of RLS: (1) an urge to move the legs usually accompanied by unpleasant sensations in the legs, (2) symptoms must be precipitated or aggravated by periods of rest or inactivity, (3) symptoms are alleviated completely or partially by movement such as walking or stretching, and (4) symptoms must be worse in the evening or at night (Hanson et al., 2004). Additional criteria that support the diagnosis include (1) symptomatic relief using dopaminergic type of medications, (2) positive for periodic leg movements in sleep, and (3) family history of RLS (Winkelmann & Ferini-Strambi, 2006).

Treatment

Treatment is aimed at minimizing the symptoms of RLS and restoring functioning to help offset the negative impact on the patient's quality of life (Satija & Ondo, 2008). In treating RLS, it is important to recognize and treat underlying causes that may be present because, in doing so, the patient may see their RLS symptoms completely resolve. Iron supplementation in the case of iron deficiency and kidney transplantation for kidney failure often work to resolve RLS symptoms and are cases that illustrate the need to address underlying conditions (Satija & Ondo, 2008). In less severe cases of RLS, it is widely reported that nonpharmaceutical therapies such as massage and hot baths can be effective to offer temporary relief of symptoms (Satija & Ondo, 2008).

Carbidopa/Levodopa (Sinemet)

The mainstays of pharmaceutical therapies for RLS are the dopaminergic medications. One of the first treatments to be used for RLS is carbidopa/levodopa, which helps to increase dopamine levels in the brain (Satija & Ondo, 2008). Carbidopa/levodopa is taken orally and, like other dopaminergic medications, has similar side effects of nausea, diarrhea, orthostatic hypotension, somnolence, and headache (Satija & Ondo, 2008). Like other dopaminergic medications, carbidopa/levodopa is limited by so-called "augmentation" where the patient will experience a worsening of symptoms and/or the onset of symptoms earlier in the day. Because of having a short half-life, carbidopa/levodopa is usually reserved for mild cases of RLS or for those with intermittent symptoms where daily medication therapy is not needed (Satija & Ondo, 2008). Total daily dosages of carbidopa/levodopa should not exceed 75/300 mg daily, and this drug is not approved by the Food and Drug Administration (FDA) for the treatment of RLS (Satija & Ondo, 2008).

Dopamine Receptor Agonists

This class of medications includes drugs such as ropinirole (Requip; first FDA-approved drug for the treatment of RLS in 2005), rotigotine (Neupro), and pramipexole (Mirapex) which work to bind with dopamine receptors to mimic the effects of dopamine in the brain (Satija & Ondo, 2008). Requip and Mirapex are oral medications approved by the FDA for the treatment of RLS and are typically administered daily before bedtime but can also have a split dosage time with part of the dose in the late afternoon/early evening and the other at bedtime. Neupro is the relative newcomer and is FDA approved for the treatment of RLS. Neupro is available in a 24-hour transdermal preparation that has shown promise with lower rates of augmentation compared with other drugs in the class (Trenkwalder et al., 2008). Common side effects include hypotension and nausea with the most troubling side effects being instances of sudden sleep episodes and rare cases of impulsive behaviors such as gambling and abnormal sexual behaviors (Satija & Ondo, 2008).

Opioids

With many patients with RLS reporting painful sensations, it is no wonder that the opioids have shown to be of significant benefit to RLS sufferers (Fulda & Wetter, 2008). With this class of medications come prescriber worries of addiction, tolerance, and dose escalation, but in the case of patients with RLS, opioids show both short- and long-term efficacy with low potential for addiction and tolerance (Winkelman, Allen, Tenzer, & Hening, 2007). Opioids are actually considered to be the optimal treatment regimen in severe cases of RLS or in cases where there has been significant augmentation with other pharmaceutical therapies (Winkelman et al., 2007). With this class of medications, administration can usually be confined to the late afternoon and evening with dosages starting low and titrated up for symptomatic relief. Despite research indicating the safety and efficacy of opioids in the treatment of RLS, the patient should be informed of the risks and benefits of long-term opioid therapy.

Benzodiazepines

Usually a second- or third-line treatment, the benzodiazepines help with the treatment of RLS by relieving residual insomnia after the resolution of symptoms with other medications but are not FDA approved in the treatment of RLS (Winkelman et al., 2007). Although not well studied in the case of RLS, the benzodiazepines can help in the achievement and maintenance of sleep, which is of particular benefit in RLS with sleep disturbance being a major aspect of the disorder (Winkelmann & Ferini-Strambi, 2006).

Antiepileptics

Although not FDA approved for the treatment of RLS, gabapentin (Neurontin) has been shown in studies to be effective in the treatment of RLS (Satija & Ondo, 2008). Neurontin shows particular promise in patients who report pain as one of their RLS symptoms, perhaps because of its benefit in other disease processes, which also involve neurological pain. (Satija & Ondo, 2008). Gabapentin enacarbil (Horizant) recently gained FDA approval for the treatment of moderate to severe RLS and is used as a once-daily medication (U.S. FDA, 2011).

An aspect of RLS treatment that should not be overlooked is the significant placebo effect that has been reported with RLS and other neurological pain disorders (Fulda & Wetter, 2008). In a 2008 metaanalysis of 24 studies including 1,527 patients, the researchers found that, on average, over one third of RLS sufferers experienced major improvement in symptoms with the initiation of placebo-based treatment (Fulda & Wetter, 2008).

Case Presentation

Case 1

RS is a 34-year-old man who was diagnosed with RLS approximately 5 years ago. He chose to seek treatment after discovering through the Internet that the symptoms he had been experiencing since early childhood were not normal and that he may in fact have RLS. He searched the Internet for a provider specializing in the treatment or RLS and was able to schedule a direct appointment with a local neurologist.

RS was diagnosed with RLS through a discussion of history with this neurologist who described his case as both severe and long standing. He was initially started on Requip 0.5 mg daily at bedtime. After 1 month of therapy, he had not obtained optimal control of his symptoms in the evening so his dosage was increased to 0.5 mg at supper and 0.5 mg at bedtime. Despite significant nausea, he was maintained on this dosage for the next 9 months with good control of his RLS. Toward the end of his first year of treatment, he began to experience augmentation along with difficulty staying asleep and persistent nausea. His neurologist recommended a dosage increase, but he choose to taper off of Requip altogether and take his chances without medication.

Within 3 months, he was in to see his primary care provider who started him on Mirapex 0.25 mg at supper and 0.25 mg at bedtime. He never achieved optimal symptomatic relief with this medication, so he was then started on hydrocodone/acetaminophen (Vicodin) 1-2 tabs daily in the evening and lorazepam (Ativan) 0.5 mg at bedtime by his primary care provider. With this medication regimen, he was able achieve the best control of his RLS symptoms to date and was maintained on this therapy for about 1 year. He then returned to the original neurologist who diagnosed him reporting the medications that he was presently taking as well as having tried and failed with Mirapex. RS reported good symptomatic relief with the Vicodin and Ativan but questioned whether he should be initiated on a long-acting opioid. His neurologist agreed that he had failed therapy with dopamine agonists and agreed that opioid therapy may be best for his case. He was started on methadone (Dolophine) 5 mg daily in the evening with Ativan 0.5 mg at bedtime and, in 1 month, titrated up to methadone 5 mg daily in the evening and 5 mg daily at bedtime, maintaining the Ativan at bedtime. He has been maintained on this same medication regimen for the last 2.5 years and has experienced neither tolerance nor addiction and continues to achieve optimal symptomatic control of his RLS.

Case 2

MS is a 64-year-old man and is the father of RS in the above case. He too has a long history of RLS symptoms dating back to early adulthood. Upon the urging of his son, MS made an appointment with the same neurologist to seek medical attention for his RLS. Beyond patient history, the neurologist recommended diagnosis via sleep study where it showed that MS had obstructive sleep apnea and that RLS was waking him many times per night. His case of RLS was also described as both severe and long standing with a familial correlation between him and his son. He was similarly started on both Requip and Mirapex and failed both of them in similar fashion to his son but was also treated with home CPAP for his obstructive sleep apnea. He too was started on both methadone and Ativan at the same dosages as his son and has experienced similar symptomatic relief of RLS without any side effects for the last 2 years.

Summary

RLS is a prevalent neurological disorder with few treatments and for which the exact mechanism has been proposed but continues to be researched. The above case reports indicate the ability of familial RLS to behave similarly in both symptomology and treatment. With a high percentage of RLS cases being familial, perhaps future research could look at whether there is a significant response to similar treatments in familial RLS. If so, it may help providers in targeting therapies to help patients get symptomatic relief in a timely fashion.

References

Fulda, S., & Wetter, T. C. (2008). Where dopamine meets opioids: A meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain, 131(4), 902-917. doi: 10.1093/brain/awm244

Hanson, M., Honour, M., Singleton, A., Crawley, A., Singleton, A., Hardy, J., & Gwinn-Hardy, K. (2004). Analysis of familial and sporadic restless legs syndrome in age of onset, gender, and severity features. Journal of Neurology, 251(11), 1398-1401. doi: 10.1007/s00415-004-0552-7

Hening, W., Walters, A. S., Allen, R. P., Montplaisir, J., Myers, A., & Ferini-Strambi, L. (2004). Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: The REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Medicine, 5(3), 237-246. doi: 10.1016/j .sleep.2004.03.006

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Trenkwalder, C, Benes, H., Poewe, W., Oertel, W. H., Garcia-Borreguero, D., De Weerd, A. W., ... Kohnen, R. (2008). Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: A randomised, double-blind, placebo controlled trial. Lancet Neurology, 7(7), 595-604. doi:10.1016/ S14744422(08)70112-l

Tzonova, D., Larrosa, O., Calvo, E., Granizo, J. J., Williams, A., De la Llave, Y., & Garcia-Borreguero, D. (2012). Breakthrough symptoms during the daytime in patients with restless legs syndrome (Willis-Ekbom disease). Sleep Medicine, 13(2), 151-155. doi: 10.1016/j.sleep.2011.09.015

U.S. Food and Drug Administration. (2011). FDA approves Horizant to treat restless legs syndrome. Retrieved from http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm250188.htm

Whittom, S., Dauvilliers, Y., Pennestri, M. H., Vercauteren, F., Molinari, N., Petit, D., & Montplaisir, J. (2007). Age-at-onset in restless legs syndrome: A clinical and polysomnographic study. Sleep Medicine, 9(1), 54-59. doi:10.1002/mds.22769

Winkelman, J. W., Allen, R. P., Tenzer, P., & Hening, W. (2007). Restless legs syndrome: Nonpharmacologic and pharmacologic treatments. Geriatrics, (52(10), 13-16.

Winkelmann, J., & Ferini-Strambi, L. (2006). Genetics of restless legs syndrome. Sleep Medicine Reviews, 10(3), 179-183. doi:10.1016/j.smrv.2006.01.003

Xiong, L., Montplaisir, J., Desautels, A., Barhdadi, A., Turecki, G., Levchenko, A., ... Rouleau, G. A. (2010). Family study of restless legs syndrome in Quebec, Canada: Clinical characterization of 671 familial cases. Archives of Neurology, 67(5), 617-622. doi: 10.1001/archneurol.2010.67

Questions or comments about this article may be directed to Scott Snider, MSN FNP, at scottmsnider@gmail.com. He is a Registered Nurse at the Inpatient/Outpatient Oncology Floor, St. Joseph's Hospital, Marsh field, WI.

The author declares no conflicts of interest.
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Author:Snider, Scott
Publication:Journal of Neuroscience Nursing
Article Type:Clinical report
Date:Dec 1, 2013
Words:2473
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