March 1999 studies

[ksxroads]

A couple of things I came across thought I'd share with the others. They are older studies, yet have some information that someone might find useful Like Ann says, take what you want, leave the rest! Hazel

from http://www.postgradmed.com/issues/1999/ ... idente.htm


What are the mechanisms that cause restless legs syndrome?
Pathogenesis of the syndrome is unclear. Karl A. Ekbom originally proposed that it was mainly the result of accumulation of metabolites in the legs from venous congestion (1-3). Peripheral nerve abnormalities have also been proposed, but no structural changes in nerve endings have been seen (4). Many experts believe that the syndrome is generated centrally (1,3,5). Periodic limb movements of sleep, in particular, are thought to be caused by sleep-related disruption of descending inhibitory reticulospinal pathways that are normally active at the brain stem or spinal cord level.

On the basis of treatment response, restless legs syndrome has been linked to dopaminergic or opiate abnormalities (3). Dopamine blockers and opiate blockers reactivate symptoms when given to patients with the syndrome. Results of single-photon emission computed tomography have suggested deficiency of dopamine D2 receptors (6). Sympathetic hyperactivity has also been implicated (5) on the basis of observations that sympathetic nerve blockade relieves periodic limb movements of sleep and that alpha-adrenergic blockers improve symptoms of restless legs syndrome. Studies also have suggested possible underactivity of the serotonin and gamma-aminobutyric acid neurotransmitter systems.

References

1. Trenkwalder C, Walters AS, Hening W. Periodic limb movements and restless legs syndrome. Neurol Clin 1996;14(3):629-50
2. Silber MH. Restless legs syndrome. Mayo Clin Proc 1997;72(3):261-4
3. Walters AS, for the International Restless Legs Syndrome Study Group. Toward a better definition of the restless legs syndrome. Mov Disord 1995;10(5):634-42
4. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996;19(5):670-2
5. O'Keeffe ST. Restless legs syndrome: a review. Arch Intern Med 1996;156(3):243-8
6. Staedt J, Stoppe G, Kogler A, et al. Dopamine D2 receptor alteration in patients with periodic movements in sleep (nocturnal myoclonus). J Neural Transm Gen Sect 1993;93(1):71-4


How to help patients with restless legs syndrome
Discerning the indescribable and relaxing the restless
Virgilio Gerald H. Evidente, MD Charles H. Adler, MD, PhD
VOL 105 / NO 3 / MARCH 1999 / POSTGRADUATE MEDICINE

CME learning objectives
• To familiarize primary care physicians with diagnostic criteria for restless legs syndrome
• To elucidate secondary, and often curable, causes of restless legs syndrome
• To describe current treatment options for restless legs syndrome


Preview: Few conditions are characterized by the difficulty encountered in trying to depict their symptoms, but such is the case in restless legs syndrome. Patients report sensations that are not painful yet are distinctly bothersome and can lead to significant physical and emotional disability. Once correctly diagnosed, restless legs syndrome can usually be effectively treated symptomatically, and in some secondary cases, it can even be cured. In this article, the authors focus on clinical features that enable timely identification of the condition and on current management strategies.

In the mid-1940s, Swedish neurologist Karl A. Ekbom described a disorder characterized by sensory symptoms and motor disturbance of the limbs, mainly during rest. He named the condition restless legs syndrome (1). Although the syndrome affects about 10% to 15% of the US population (2), it is often unrecognized and misdiagnosed. It may begin at any age (1-3), even as early as infancy, but most patients who are severely affected are middle-aged or older. Symptoms progress over time in about two thirds of patients and may be severe enough to be disabling.
Diagnostic criteria and common features

In 1995, the newly formed International Restless Legs Syndrome Study Group developed criteria for diagnosing restless legs syndrome (3). Four basic elements must be present to make the diagnosis: (1) a desire to move the limbs, often associated with paresthesia or dysesthesia, (2) symptoms exacerbated by rest and relieved by activity, (3) motor restlessness, and (4) nocturnal worsening of symptoms. These and several additional features commonly seen in restless legs syndrome are discussed in the following paragraphs.

• Desire to move the limbs, paresthesia, dysesthesia. Patients often describe an unpleasant sensation in the calves and occasionally in the thighs, feet, or upper limbs. Although the study group refers to dysesthesia or paresthesia (which implies abnormal sensations) (3), most patients simply relate vague, nonpainful, indescribable, bilateral (rarely unilateral) discomfort in the limbs, using such terms as crawling, creeping, tingling, burning, itching, and aching.

Symptoms are similar to those described by patients with akathisia (which is usually caused by use of neuroleptic drugs). However, in contrast to patients with restless legs syndrome, those with akathisia have an inner feeling of restlessness, gain the most relief by resting in a recumbent position, and do not experience paresthesia or nocturnal worsening of symptoms.

• Symptoms exacerbated by rest, relieved by activity. The unpleasant limb sensations of restless legs syndrome are precipitated by rest or inactivity (eg, lying in bed at night, riding in a car or airplane, sitting in a theater). The discomfort is usually relieved by motor activity (eg, moving the legs, walking).

• Motor restlessness. Patients describe a buildup of discomfort and involuntary limb jerking if they remain still. There is an urge to move the legs and relief after moving (much like the sensation of tics). Compelling motor restlessness can manifest as tossing and turning in bed, needing to pace the floor, stretching or shaking the legs, or needing to exercise (3). Limb movements in restless legs syndrome are partly voluntary, in that patients choose to move to relieve the discomfort, and partly involuntary, since patients are compelled to move. Such partly voluntary, partly involuntary movements are sometimes referred to as "unvoluntary" or "semivoluntary."

• Nocturnal worsening of symptoms. All patients notice worsening of symptoms at night (usually as they lie in bed before sleep or when they are awakened in the middle of the night) and improve-ment early in the morning. Nocturnal worsening is caused by lack of motor activity at night and is also thought to be due to an independent circadian rhythm (3). In severe cases, patients experience symptoms both day and night.

• Periodic limb movements of sleep. About 80% of patients with restless legs syndrome have unilateral or bilateral periodic limb movements of sleep, also called nocturnal myoclonus (1,3). These movements are stereotyped, repetitive, slow flexion of the limbs (legs alone or legs more than arms) during stage 1 or 2 sleep. They occur semirhythmically at intervals of 5 to 60 seconds and last about 1.5 to 2.5 seconds. In the lower limbs, repetitive dorsiflexion of the big toe with fanning of the small toes is seen, along with flexion of the ankles, knees, and thighs.

• Dyskinesias while awake. These motions, also called periodic limb movements while awake, are seen in 30% to 50% of patients with restless legs syndrome (3). They are similar to periodic limb movements of sleep but occur only during wakefulness. They can be fast or slow and periodic or nonperiodic.

• Sleep disturbance. Because of limb discomfort and jerking, most patients with restless legs syndrome have disturbances of sleep onset or maintenance (1,3). The result is excessive daytime sleepiness and fatigability, although not to the same degree as that caused by narcolepsy.

Primary disease

In most cases, restless legs syndrome is idiopathic. Such idiopathic disease can be familial (in 25% to 75% of cases) and, if so, is transmitted in an autosomal-dominant fashion (1,3,4). Progressive decrease in age at onset with subsequent generations (ie, genetic anticipation) has been described in some families. Patients with familial restless legs syndrome tend to have an earlier age at onset and slower progression (5).

Secondary disease

Restless legs syndrome can develop as a result of certain conditions or factors (table 1), particularly iron deficiency and peripheral neuropathy (6-12). These two conditions should be ruled out on clinical grounds before restless legs syndrome is labeled primary (13). Because of the prevalence of these conditions in the general population, their association with restless legs syndrome needs to be interpreted with considerable caution.
Table 1. Factors and conditions that may contribute to secondary restless legs syndrome (in order of frequency)

Deficiency of iron, folate, or magnesium
Polyneuropathy caused by alcohol abuse, amyloidosis, diabetes mellitus, idiopathic polyneuropathy, lumbosacral radiculopathy, Lyme disease, monoclonal gammopathy of undetermined significance, rheumatoid arthritis, Sjögren's syndrome, uremia, or vitamin B12 deficiency
Pregnancy
Anemia
Parkinson's disease
Gastric surgery
Chronic obstructive pulmonary disease
Carcinoma
Chronic venous insufficiency or varicose veins
Intake of certain substances or drugs: alcohol, caffeine, anticonvulsants (eg, methsuximide [Celontin Kapseals], phenytoin [Dilantin]), antidepressants (eg, amitriptyline HCl [Elavil], paroxetine HCl [Paxil]), beta blockers, histamine2 antagonists, lithium, neuroleptics
Withdrawal from vasodilators, sedatives, or imipramine HCl (Tofranil)
Cigarette smoking
Myelopathy or myelitis
Hypothyroidism or hyperthyroidism
Acute intermittent porphyria
Fibromyalgia syndrome
Arborizing telangiectasia of the lower limbs
Peripheral microemboli made of cholesterol

Restless legs syndrome can be the initial manifestation of iron deficiency (1,14). A low serum ferritin level may precede a drop in serum iron level. Depletion of iron stores, in the absence of overt iron deficiency, can lead to restless legs syndrome. How this occurs in unknown. Treatment with ferrous sulfate may bring improvement.

About 5% of patients with sensory neuropathy (especially caused by uremia, rheumatoid arthritis, and diabetes) have restless legs syndrome (8). Treatment of the polyneuropathy may improve symptoms.

Diagnosis
Diagnosis of restless legs syndrome is founded mainly on clinical history. If a secondary cause is suspected on the basis of history, abnormal findings on neurologic examination, or poor response to treatment, a laboratory workup should be done. Testing should measure levels of blood urea nitrogen, creatinine, fasting blood glucose, ferritin, magnesium, thyrotropin, and folate and should include a glucose tolerance test and a complete blood cell count.

Needle electromyography and nerve-conduction studies should be considered if polyneuropathy is suspected on clinical grounds, even if results of neurologic examination are apparently normal (13). Polysomnography is rarely necessary but may be used to quantify periodic limb movements of sleep or to characterize sleep architecture, especially in patients who continue to have significant sleep disturbance despite relief of sensory symptoms with treatment.

Nonpharmacologic management
Patients with suspected restless legs syndrome who are sensitive to caffeine, alcohol, or nicotine should avoid these substances (1,6). Offending medications (table 1) also should be discontinued. In general, physical measures are only partially or temporarily helpful. Some patients benefit from hot or cold baths, whirlpool baths, rubbing of the limbs, or vibratory or electrical stimulation of the feet and toes before bedtime.
Supplementation to correct deficiencies in vitamins (eg, folate) (15), electrolytes (eg, magnesium) (7), or iron may improve symptoms. Patients with prominent varicose veins in the legs may benefit from use of sclerosing agents (9). Those with uremia may have relief after kidney transplantation or correction of anemia with erythropoietin (Epogen, Procrit) (6).

Pharmacologic management

Drug therapy for primary restless legs syndrome is largely symptomatic, since cure is only possible in secondary disease. Medications should be initiated at a low dose and be taken an hour or two before bedtime to allow sufficient absorption and onset of action. Additional doses can be taken if symptoms cause awakening in the middle of the night. If tolerance to one drug develops, another class of drugs may be substituted. Monthly rotation of two or three agents found to be effective may help prevent tolerance. A combination of drugs may be beneficial in severe cases.

Levodopa with carbidopa Levodopa with carbidopa (Sinemet) can improve sensory symptoms and periodic limb movements of sleep in primary restless legs syndrome and that associated with uremia (1-3,16). For symptoms that start before sleep, one 25/100-mg carbidopa/levodopa tablet can be taken 1 to 2 hours before bedtime. If symptoms occur during the night, one 25/100-mg controlled-release carbidopa/levodopa (Sinemet CR) tablet can be used. In patients who have symptoms both before sleep and during the night, a combination of short-acting and controlled-release tablets can be given. Most patients experience benefits when the levodopa portion of carbidopa/levodopa totals 100 to 500 mg daily, although some may need 1,000 to 1,500 mg. Nausea and constipation are the most common side effects of levodopa.

The major drawback in prescribing levodopa for restless legs syndrome is that in about 80% of patients, augmentation of symptoms occurs as early as a few months after initiation of therapy (17). It can manifest as earlier onset during the evening or after assuming a restful position, as increased intensity in the morning (ie, rebound), or as extension of symptoms to the upper body. Augmentation is more likely in patients with severe pretreatment symptoms and in those taking 200 mg or more of levodopa daily. If augmentation or rebound develops, adjunctive therapy with reduction of the levodopa dose or discontinuation of levodopa and substitution of another drug may help.

Dopamine agonists Dopamine agonists are less likely to produce augmentation or rebound and can be useful alone or along with levodopa in patients in whom one of these conditions develops (2,17,18). Side effects of dopamine agonists include nausea, light-headedness, drowsiness, and postural hypotension.

Pergolide mesylate (Permax) is a potent, long-acting dopamine D1 and D2 receptor agonist that has been shown to be effective in restless legs syndrome (1-3,16), even in patients who are unresponsive to levodopa (18). The dose is 0.05 mg before bedtime initially, and it can be increased by 0.05 mg every 3 to 5 days until relief is obtained or side effects develop. The usual effective daily total is 0.1 to 0.75 mg, given in divided doses; some patients may need up to 1.5 mg.

Bromocriptine mesylate (Parlodel), a dopamine D2 receptor agonist, also has been found to be effective in restless legs syndrome (1-3,18). Bromocriptine can be started at a dose of 1.25 mg at bedtime and increased by 1.25 mg every few days until benefits or side effects are noted. The effective daily dose ranges from 5 to 15 mg.

Pramipexole (Mirapex), a dopamine D2 and D3 receptor agonist, and ropinirole hydrochloride (Requip), a dopamine D2 receptor agonist, were recently approved by the Food and Drug Administration for treating Parkinson's disease. Pramipexole is started at 0.125 mg at bedtime and gradually increased to a maximum of 1.5 mg three times daily. Ropinirole is started at 0.25 mg and increased to 3 to 8 mg three times daily (19,20).

Benzodiazepines Benzodiazepines may be used as monotherapy in patients with mild or intermittent symptoms or as add-on therapy in severe cases. Clonazepam (Klonopin) has been shown to ease the sensory symptoms and periodic limb movements of sleep in restless legs syndrome (1-3,16). The agent can be started at 0.25 mg at bedtime and increased by 0.25 mg every week to a maximum of 3 to 4 mg daily in divided doses. Anecdotal reports indicate that other benzodiazepines, such as temazepam (Restoril) and alprazolam (Xanax), are also effective. The major side effects of benzodiazepines include daytime drowsiness and confusion, unsteadiness and falls, and aggravation of sleep apnea.

Opioids Low-potency opioids, such as codeine and propoxyphene (Darvon, Dolene), can benefit patients with mild and intermittent symptoms, and higher-potency agents, such as oxycodone hydrochloride (Roxicodone), methadone (Dolophine) hydrochloride, and levorphanol tartrate (Levo-Dromoran), may have a role in refractory cases (1-3,16). In a double-blind, placebo-controlled study, oxycodone (mean daily dose, 15.9 mg) was found to be more effective than placebo (21). However, most physicians are hesitant to use opioids in restless legs syndrome because of the perceived risk of addiction and do so only in refractory cases.

Anticonvulsants Double-blind studies have shown that carbamazepine (Tegretol), at a dose of 200 to 400 mg daily, is effective in reducing sensory manifestations of restless legs syndrome (1-3,16), especially among young patients with recent onset of disease and severe symptoms. Unfortunately, subsequent clinical experience has not shown convincing efficacy of carbamazepine.

Open-label studies have found gabapentin (Neurontin) to be effective in relieving sensory symptoms (22) and periodic limb movements of sleep, even in refractory cases. The drug can be initiated at a dose of 100 to 300 mg at bedtime and increased by 100 to 300 mg every 3 days to a maximum of 2,400 mg daily in divided doses. Gabapentin is usually well tolerated but may cause transient or mild side effects, such as somnolence, dizziness, ataxia, and fatigue.

Presynaptic alpha2-adrenergic agonist Clonidine hydrochloride (Catapres) may be effective in primary restless legs syndrome and that associated with uremia (1-3,16). The drug should be started at 0.1 mg at bedtime and can be increased every week by 0.1 mg to a maximum of 1 mg daily (average effective daily dose, 0.5 mg). Among the common side effects are dry mouth, decreased cognition, light-headedness, sleepiness, and constipation.

Summary
Restless legs syndrome is a common, potentially disabling condition that affects about 10% to 15% of the general population and yet is often unrecognized and misdiagnosed. It is mainly diagnosed clinically and only rarely requires polysomnography. The condition is usually primary and treatable. First, however, secondary causes should be sought, especially iron deficiency and peripheral neuropathy, because when the source is an accompanying factor or condition, the syndrome may be curable. The most effective drugs are dopaminergic agents, clonazepam, opioids, gabapentin, and clonidine. Additional agents are available that may be beneficial as add-on or alternative therapy.

References
1. Trenkwalder C, Walters AS, Hening W. Periodic limb movements and restless legs syndrome. Neurol Clin 1996;14(3):629-50
2. Silber MH. Restless legs syndrome. Mayo Clin Proc 1997;72(3):261-4
3. Walters AS, for the International Restless Legs Syndrome Study Group. Toward a better definition of the restless legs syndrome. Mov Disord 1995;10(5):634-42
4. Trenkwalder C, Seidel VC, Gasser T, et al. Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996;11(4):389-94
5. Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology 1996;47(6):1435-41
6. O'Keeffe ST. Restless legs syndrome: a review. Arch Intern Med 1996;156(3):243-8
7. Popoviciu L, Asgian B, Delast-Popoviciu D, et al. Clinical, EEG, electromyographic and polysomnographic studies in restless legs syndrome caused by magnesium deficiency. Rom J Neurol Psychiatry 1993;31(1):55-61
8. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996;19(5):670-2
9. Kanter AH. The effect of sclerotherapy on restless legs syndrome. Dermatol Surg 1995;21(4):328-32
10. Sanz-Fuentenebro FJ, Huidobro A, Tejadas-Rivas A, et al. Restless legs syndrome and paroxetine. Acta Psychiatr Scand 1996;94(6):482-4
11. Drake ME. Restless legs with anti-epileptic drug therapy. Clin Neurol Neurosurg 1988;90(2):151-4
12. Metcalfe RA, MacDermott N, Chalmers RJ. Restless red legs: an association of the restless legs syndrome with arborizing telangiectasia of the lower limbs. J Neurol Neurosurg Psychiatry 1986;49(7):820-3
13. Iannaccone S, Zucconi M, Marchettini P, et al. Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995;10(1):2-9
14. O'Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing 1994;23(3):200-3
15. Botez MI, Lambert B. Folate deficiency and restless-legs syndrome in pregnancy. N Engl J Med 1977;297(12):670
16. Krueger BR. Restless legs syndrome and periodic movements of sleep. Mayo Clin Proc 1990;65(7):999-1006
17. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19(3):205-13
18. Earley CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep 1996;19(10):801-10
19. Ondo W. Ropinirole for restless legs syndrome. Mov Disord 1999;14(1):138-40
20. Lin SC, Kaplan J, Burger CD, et al. Effect of pramipexole in treatment of resistant restless legs syndrome. Mayo Clin Proc 1998;73(6):497-500
21. Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993;16(4):327-32
22. Adler CH. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol 1997;20(2):148-51

[searching_gurl]

Anticonvulsants Double-blind studies have shown that carbamazepine (Tegretol), at a dose of 200 to 400 mg daily, is effective in reducing sensory manifestations of restless legs syndrome (1-3,16), especially among young patients with recent onset of disease and severe symptoms. Unfortunately, subsequent clinical experience has not shown convincing efficacy of carbamazepine.

This worked for me last night, does the above say that it will stop working over time or that I caught it in time for this drug to be effective?

[moonlight]

Hi

Don't know if you ever check out the drugs, I just checked the one youre talking about on the FX list ,in the section ..warnings..

Quote:
Anticonvulsants Double-blind studies have shown that carbamazepine (Tegretol), at a dose of 200 to 400 mg daily, is effective in reducing sensory manifestations of restless legs syndrome (1-3,16), especially among young patients with recent onset of disease and severe symptoms. Unfortunately, subsequent clinical experience has not shown convincing efficacy of carbamazepine.

huggles
moonlight [/quote]

[Aiken]

Progressive decrease in age at onset with subsequent generations (ie, genetic anticipation) has been described in some families.

Hmm, no significance to me, since I'm already here and I'm not expecting to have any offspring, but this is pretty disturbing for some up-and-coming generations.

[KBear]

I think it may be a matter of "awareness". I didn't know enough to look for symptoms of RLS in my daughter while she was growing up. If I knew then what I know now I would have been on the look out for restless sleep, growing pains, difficulty sitting still for long car rides, etc.

Fortunately my daughter has made it to the ripe old age of 23 with no signs of RLS. I hope this continues for her.

[SquirmingSusan]

Neither of my kids have shown any signs of having RLS either. My daughter is 18 and my son is 16, and both of them sleep very well through the night and neither have odd sensations or growing pains. They have other issues, most of which can be summarized by saying that they're teenagers.

So maybe it isn't a given that kids of RLSers will have RLS.

[becat]

You Know,
Kathy, I thought the same thing. Looking backwards at it all, it was so plain and simple. My youngest was me all over again, minus (thankfully) the pain.

He took so much crap at school for not staying on task, while at night I could here him fight the bed he was trying to Sleep in. Poor guy, but I didn't know what was wrong with either of us.

It sorta breaks my heart, as I can not take blame for genetics I had no idea I had. I could have done more or something different, so much earlier if I had known.

It was still so hard after I put the puzzle togther, no one understands sleep deprivation on the scale many of us have.

Aiken, in my family, you might already know that both my mom and dad have RLS to some degree. I couldn't tell you much about my dad's side, most of my relatives have passed. He was the youngest of 9 and a niece 4 yrs older than him.
LOL did that sound Southern or what!LOL (sorry made myself laugh)

Ok, so anyway, it seems that on Moms side there is a clear severity trait that skips a generation. My grandmother's grandmother, I believe had it madly and painfully. I know she spent a great deal of time in bed, and suffered pain Often.

My grandmother ( beloved and best friend ever) had it like I do. Tough, painful, and no less than 19 hours a day.

But my mother and her siblings do not seem to have it like I do, nor my son. Mom and her siblings ( not all) had growing pains, but out grew them. We're still a family of Movers, trust me, but only after they have aged has it come back in a mild manner.

My mom had a 4-6 yrs stretch, before I was born, that was just awful. It's a horrid story and it's classic RLS, but she would be so exhausted after days and days of insomnia, she would simple scratch in her sleep....to the point of major injury.
Sad, I know.

However, she rarely has problems with it now.

So, it's for my future grandchildren, that I poke at the community's doctors and researchers to hurry up already! LOL
For all our children, and just maybe in time for us too!

Hugs to all Lynne

[psychick]

Progressive decrease in age at onset with subsequent generations (ie, genetic anticipation) has been described in some families.

Hmm, no significance to me, since I'm already here and I'm not expecting to have any offspring, but this is pretty disturbing for some up-and-coming generations.

My grandmother had very severe RLS and my father suffered from it as well. This is anecdotal as neither of them is alive any longer, but my mother knew them both well (as you might guess by my existence) and she and I have talked about it. As for genetic inheritance, I take after my paternal family stronger than my maternal side (physical resemblance, health traits, and some personality/emotional traits as well), so it's no surprise to me that I'm (at least) the third generation in a long line of RLS/PLMD sufferers.