CHAPTER IO

RESTLESS LEGS S\C{DROME,

Robert M. Goecker, DPM

DEFINITION AND CLINICAL FEATT]RES

The restless legs syndrome (RLS) is a neuroiogic dis-order that is characterizedby unpleasant dysestheticor paresthetic sensations in the legs that occur at restespecially at bedtime (night). The dysesthesias maybe described as pins and needles, an internal itch, orcirawing, creeping, crawling sensations in the calvesand legs. These symptoms caLlse an irresistible urgeto move.l Movement of the legs or walking oftenyields prompt relief. Due to the night timesymptoms it is common that patients with RLS havedelayed sleep onset, leading to insomnia ancl

chronic mild sleep loss.'RLS is primarily a clinical diagnosis.'i The

minimal criteria for diagnosis are presented in Table1. The first, a desire to move the extremities, oftenassociated with paresthesias or dysesthesias, is

usually experienced as "deep seated" and does notaffect the skin. The calves are the most frequentlyaffected area, but it can be felt in the thighs and feetas well. Some patients actually only describe this as

a need to move the legs without paresthesias.Another criteria, motor restlessness, occllrs duringw-akefulness where patients move to relieve thediscomfort in the legs. The movements atevoluntary, but the compelling urge to move is

involuntary. Third, is a worsening of the signs andsymptoms at rest with at least temporary relief byactivity. Patients often turn to pacing, leg stretches,

marching, body rocking, tossing and turning in bed,

Table 1

CLINICAL CTIARACTERISTICS OF RLSNECESSARY FOR DIAGNOSIS

(MINIMAI CRITERIA)

1. Desire to move the limbs usr-rally associatedwith paresthesias/dysesthesias.

2. NIotor restlessness.

3. Symptoms are worse at rest (i.e., lying, sitting)with at least temporary relief by activity.

4. Symptoms are worse in the evening or night.

or hot/cold baths to counteract the leg sensations.

Finally, there is a worsening of the symptoms at night.This seems to be secondary to an independent circa-dian factor where the sensations are worse at nightand are absent or less disturlting in the morning.6'

The past 2 decades have shown a substantialincreased interest in RLS research groups. In the last10 years in particular there has been a significantamount of research on RLS in regarcl to prevalence,etiologies, pathophysiology, and treatment. This has

led to a better understanding of this condition. Thispaper will review the most recent insights of thepathogenesis, epidemiology, associated features,and treatment options.

PATHOGENESIS

The pathogenesis of RLS is better understood in the21st century although the exact neurophysiologicaspects of idiopathic RLS are stil1 in question. Inmost instances, the cause of RLS is unknown. This isgenerally referred to as idiopathic RLS. ClinicalsLrlveys of idiopathic RLS patients have shown thatup to 600/o of the patients repofi a positive familyhistory.8 An autosomal dominant mode of inheri-tance is suggested, and is sometimes present.e Some

genetic studies have lead to a few possible areas thatmay predispose patients to this disorder. Inpafiicular, genes encoding for the GABA A receptorsubunits, the gene for the alpha 1 receptor ofthe glycine receptor and genes involved indopaminergic transmission and metabolism have

been analyzecl but no significant consensus has

been repofied.'Research seems to suggest that the endoge-

nous dopaminergic system seems to be intimatelyinvolved in the pathogenesis of RLS.: Studies revealthat dopaminergic drugs suppress the signs andsymptoms of RLS, while dopamine antagonists(e.g., Pimozide) reactivated the symptoms andreversed the beneficial effect of the agonists.l'r

Further slrpport for the dopaminergic role inRLS can be inferred from 3 clinical features of RLS.

First, the circadian pattern to the RLS symptomscorresponds with the diurnal variation in human

62 CHAPTER 10

dopamine leve1s.6' Second, an increased frequencyof RLS with age corresponds to the generaldecrease in the dopaminergic system with aging.3Fina1ly, iron deficiency, although not a commoncalrse, is an impofiant, treatable cause orexacerbating factor of RLS.'',, Iron supplementationhas improved RLS symptoms in those with an irondeficiency.'2 1r The relevance of iron to RLS may beits role as a cofactor for tyrosine hydroxrylase,which is the tate limiting enzyme for theproduction of dopamine.

The most commonly excepted causes ofsecondary RLS are iron deflciency anemia,,,,apregnancy,'i" end stage renal disease (uremia),,8,,e

and polyneurop2thy.zo:t Iron deficiency as asecondary cause of RLS has been repofied to bemore common in patients with late onset RLS.1, Irondeficiency anemia is more comlrton with age.O'Keffe found a 220/ct incidence of iron deficiency(serum ferritin <50 ng/m1) in RLS patients before theage of 50 and e 390/o incidence between 50 to 64 andfinally a 5\o/o incidence in patients greater than64-years-o1d.'3 If serum ferritin levels are low, ironsupplementation has been shown to help thesymptoms of RLS.''

Pregnant women have at least a 2- to 3-timeshigher risk of experiencing RIS than the generalpopulation. Epidemiologic studies have shown aprevalence of 71-27o/o of RLS during pre€anancy.Usually the symptoms are worse during the thirdtrimester. The cause of the association betweenpregnancy and RLS is unknown. The most commonhypotheses are: metabolic alterations in regard toiron or folate deficiency; increasing hormones latein pregnancy and the changing motor habits andpsychological state of pregnant women.l: "

Other testimonials have linked vascular insuffi-ciency," COPD,'o lumbar spinal stenosis,2f' differentperipheral polyneuropathies,le radiculopathies,3caffeine abuse,23 pafiial gastrectomy,z'i rheumatoidafihritis,2t Mg deficiency,'z6 cliabetes" and Parkinson'sdisease2T as causes of secondarv RLS.

EPIDEMIOLOGY

In 1960, Ekbom' estimated thar RLS affectecl 5o/o ofthe population, but further repofis consider thisfigure to be too low. Research notes RLS has aprevalence ranging from 2.5 to 750/o of the generalpopr-r1ation.']s ro The largest population questionnaireof 23,052 patients had at a 9.60/o rate of RLS

symptoms at least weekly. Of these patients, 88.40/o

had some form of sleep related symptom. Mostpatients complained of insomnia due to the RLS.'Ze

There is a female predominance. Vomen are twiceas often affected as men.31 Determining the exactfrequency is difficult because symptomatologyvaries in intensity frorn patient to patient, and onlysevere cases seek medical attention. RLS may beginat any age and it may or may not occur on a dailybasis. The most severely affected patients aremiddle-aged or older with increasing severity in theelclerly.r'r RLS may be static or progressive and isgenerally chronic, although remissions may occlrr.

ASSOCIATED CLINICALFEATIJRES OF RLS

Other f'eatures commonly seen in RLS include sleepdisturbances, periodic limb movements of sleepand similar involuntary movements while awake.With sleep disturbances, many patients note a

difficulty initiating sleep, maintaining s1eep, day-time fatigue or exhaustion and, less commonly, andexcessive daytime sornnolence.

Approximately B0% of patients with RLS alsoexperience stereotyped repetitive movements onceasleep, a condition known as periodic limbmovements of sleep (PLMS).'. PLMS, (nocturnalmyoclonus), usually affects the legs alone, orthe legs more than the arms. They are typicallycharacterized by stereotypic, periodic movementsoccurring in long "trains" during s1eep. The patientexhibits dorsiflexion of the hallux and ankle withfanning of the small toes, accompanied by theflexion of the knee and hip (Babinski-like move-ment).r2 The movements may be recorded byelectromyographic studies made from both tibialisanterior muscles. They are slower than a truemyoclonic jerk (<250 ms) and are noted to recurevery 5 to 90 seconds with a duration of 0.5 to 5

seconds per movement. These movements usuallyoccur in the first and second stages of sleep, may beunilateral or bilateral, and the appearance can bevariable.'u

Periodic movements, while awake, are verysimilar in appearance to the PLMS, however, themovements disappear on voluntary movement. Thepatients use the voluntary movement to suppressthe involuntary activity. Therefore, many timesthese movements may be hidden until forcedimmobilization tests are performed.33

CHAPTER 10 63

I/.BORATORY FINDINGS

Laboratory stuclies may help docutnent anyassociated ceuses of RLS. In most patients, completebloocl counts ancl iron, f-erritin, folate and vitaminB12 levels are normal." However, the labs are

useftrl to rule out anemia. The most criticallaboratory test woulcl be a serum ferritin < 50

ng/m1.'r Other secondary causes of the disease rnay

be clocumented as we1l. For ex:rmple, abnormalENIG and NCV studies m21y be evident secondaryto peripheral neuropathy (diabetes, etc.) orradiculopatfiiss.zLt:t Idiopathic RLS usually has a

normal neurological examination with normal EMG

and NCV studies.3Polysomnography can help slrppofi the

cliagnosis of RLS by documenting sleep distur-bancesas well as periodic limb movemenm of sleep TPLMS ).

The usual polysomnographic features show a delayin sleep onset, or lxay less often show prolongedarousals usually associated with subiective restless

1"g complaints. In some patients, frequentquasiperiodic rnovements cluring wakefulness are

obserr.ed that become more stereotyped andperiodic as sleep is achieved, at nhich point PLMS

may emerge."

DIFFERENTIAL DIAGNOSIS

In most cases the clifferentiation of RLS from othercondrtions is straight-forrvald. One of the moreproblematic differenti:ltions is that between RLS

ancl small fiber peripheral neuropathies, such as

those occurring in diabetes.r0 This is the patientpopulation in our practices that is critical toappropriately cliagnose especially since there is a

higher incidence of RLS in diabetics.l' Thesepatients may have similar symptoms to RLS, how-ever, they usually persist dur1ng walking when theRLS symptoms wor-r1d subside.

Another condition in the differential diagnosisof RLS is know-n as neuroleptic-incluced akathisia(NIA). This is a motor restlessness induced bydopamine receptor blocking antipsychotic agents.

NIA differs from RLS in the following ways:movements are usually incluced by an inner rest-

lessness rather than leg paresthesias, symptoms are

not necessarily w'orse at rest or at night, patients mayeven prefer the lying position, finding the symptomsare much better than when they are standing orsitting, PLMS and sleep clisturbances are less

commonl body rocking is the typical moYementdescribecl in NIA, and a history of neuroleptic intakew'ou1d be present.r'

Other conditions in the differential diagnosisinclr-rde peripheral vascular clisease (PVD), andsimple cramps. P:rtients with PVD may experiencerest pain ancl night cramps secondary to vascularinsufficiency, zrnd can be easily differentiated fromRLS with an appropriate physical examination.Simple cramps are a frequent phenomenon innonnal as well as patholopJic conclitions. There are

spontaneous nigl-tt cramps. cramps occurring n'hileawake without apparent stimulus, or crampsoccurring as a result of a r.oluntary effort. There is

usually an altered physiologic balance zrssociated

lr,,ith cramping. Cramps may be terminated withfbrceful stretching of the contractecl muscle orby actil.ation of the zrntagonist muscles. Simplecramping r-Lsually results in a palpable muscle con-traction (i.e., Charlie horse) noted by the patientstl-rat helps distingr-rish simple cramps from RLS."'

TREATMENT

A practical approach to management involves a

stepwise plzrn. Nonpharmacologic trezrttnents center

on zrvoiding alcohol, caffeine, tobacco, and stress.

Various pharmacologic agents have been proposedfor the treatment of RLS and PLMS. Dopaminergicagents har.e become the most commonly prescribedmedicines for the treatment of RLS. These includedopamine preclrrsors (L-dopa) and dopamineagonists (pergolide, pramipexole, cabergoline and

ropinirole). L-dopa itself aln'ays is used in conjunc-

tion with dopa decarboxylase inhibitor such as

carbidopa." The efficacy of these clopaminergicagents have been reported in several studies.r54' It isimportant to note that L-dope/catbidopa mayrequire a seconcl dose in the midclle of the night sec-

ondary to its shofl half'-1ife.36 Although treatmentrvith ler.odopa allevizttes the symptoms, many RLS

patients clevelop rebound (occr:rrence of symptomsduring the night) or augmentation (occurrence ofsymptoms before levodopa closing in the evening).Augmentation has been shon'n to occllr in es manyas B2o/o of the patients treated with levodopa, limit-ing the usefulness of this agent. The directdopamine receptor agonists are longer acting drugs

that require only a single nighttime dose. These have

replaced levoclopa/czlrbiclopa as the mosr effective

treatment for RLS. Success rates between 70 to 100%o

64 CHAPTER 10

have been described with these dopamine agonists.'1'At the time this article was written, the only FDAapproved agent for RLS is ropinirole.roto Otherdopamine agonists are trying to get approval andcan be tried off-1abel.a1

Bogan et al showed ropinirole was a sllccess-fu1, well-tolerated dopaminergic medication in a

double-biind, placebo-controlled, flexible dosestudy showing a statistically significant decrease inRLS symptoms and subjective measures of sleep,quality of life ancl anxiety.3e A similar double-blind,randomized, placebo-controlled stucly by Waiters etal showed similar olltcomes 2 years previously.i'Al1en et al showed ropinirole decreases PL&IS andimproves sleep parameters in patients with RLS.40

There have been no reports of augmentation withropinirole. Patients usually need to take theirmedication 1 to 3 hours prior to bedtime for it tobe effective. The dose of ropinirole starts low andis titrated Llp to a level of efficacy. The usual startdose is 0.25 mg at night titrating up as high as 4mg/ day based on response to the therapy. Theauthor usually sees improvement in patients with a

dose of 1 mg.Normal adverse events associated with

dopaminergic medications have been reportec1.38*'

These usually include somnolence, nausea/vomiting, dizziness, and fatigue. There is a report inthe dental literature of increased dental disease inpatients on dopaminergic medications due tothe decrease in saliva production from the RLS

medications.'12

Benzodiazepines were among the medicationsfirst repofied to be useful for treating PLMS and RLS.

Clonazepam has always been the favored benzodi-azeprne, and when administered before bedtime hasbeen shown to be eff-ective.'i3 However, excessivedayime drowsiness has been reported suggestingthat a shofier half-life benzodiazepine may benecessary, such as Temazepam or Triazolam.aa

Opiates such as oxycodone, propoxyphene,and codeine have been effective in the treatment,however, potential for abuse, probiems withconstipation and the development of intolerancehave made physicians more reluctant to prescribethis therapy for long-term Lrse.3,*5 Another deterrentto usin5I opiates is their short half lives, which leadsto rebound and a second nighrtime closing unlessa longer acting opioid is used.

Catbamezapine, an anticonvulsant, proved tobe an effective treatment in double-blind studieswith reduction of the RLS symptoms.i6 Also, therehave been reports abor-rt the efficacy of other anti-convulsant agents, such as valproate sodium andgabapentin in patients with PLMS and RLS respec-tively. These agents generally are tried once theinitial therapy fails.'u

Pelletier et al state successful treatment requiressuppression of both the sensory and motorcomponents of RIS due to their independentmanifestations.3r In some difficult cases, combinationtherapies from the 3 favored classes have beenconsidered necessary as well."

CONCLUSION

The definition of and minimal criteria for diagnosisof RLS have been presented. A review of the lastseveral years of research continues to lead to a

better understanding of the pathophysiology anddopaminergic role in idiopathic RLS. Possiblesecondary causes of RLS were also mentioned. Thecurrent literature suggests idiopathic RLS may befami1ia1, with an autosomal dominant mode ofinheritance, ancl it is much more prevalent thanrecognized. It is sti11 aL under-diagnosed andunder-treated condition. The information presentedwill enable the podiatric physician to be moreconscious of RLS and PLMS, make a properdiagnosis, initiate treatment, or make arr

appropriate referral.

CHAPTER 10 65

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