RLS Associated with Spinal Cord Lesions

There are numerous case reports describing the onset of RLS in close temporal association with spinal pathologies such as lumbosacral radiculopathy (73), borrelia-induced myelitis (74), transverse myelitis (75), vascular injury of the spinal cord (76), multiple sclerosis (77), traumatic lesions (77), cervical spondylotic myelopathy (77), or syringomyelia (77). After spinal anesthesia, 8.7 of 161 patients developed transient new onset RLS (78). Many subjects in these reports responded to...

Pathology of Restless Legs Syndrome

Department of Neurosurgery, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, U.S.A. This chapter will focus on the results of postmortem evaluations of brains from individuals with restless legs syndrome (RLS). The autopsy analyses involved standard histological evaluations of the brain and a more detailed focus on parameters associated with iron status in the substantia nigra. The substantia nigra was chosen because of magnetic...

Normal Sleep Architecture And Sleep Stages

Sleep can be divided into two states nonrapid eye movement (NREM) and rapid eye movement (REM) sleep. Each cycle of NREM and REM sleep lasts approximately 90 to 110 minutes, and about three to six cycles of NREM-REM sleep occur during a normal night of sleep (Fig. 1). Slow wave sleep (SWS), which will be discussed in more detail later, tends to dominate the first third of sleep, whereas REM sleep is most predominant in the last third of sleep. The first REM cycle is typically short the final...

Functional Anatomy Of Central Dopamine Systems

It has now been some 40 years since a group of Swedish scientists first described the nigrostriatal, mesocorticolimbic, and tuberoinfundibular dopamine neurons as giving rise to the three most conspicuous and behaviorally relevant dopamine circuits in the brain (19). Using histofluoresence and subsequently immunohistochemical identification of TH (20,21), 16 unique monoaminergic cell groups were identified and given designations A1-A16. Dopamine has been identified as the major transmitter in a...

The Spinal Cord

Involvement of the spinal cord in the pathophysiology of RLS is suggested by the fact that sensory and motor symptoms are bilateral and segmentally localized in the legs in most cases. Possibly, either a sensory signal from the periphery to the sensory cortex is affected at the level of the spinal cord or the abnormal input itself is generated at that level. The two major lines linking RLS and PLMS to the spinal cord are observations of both phenomena in association with spinal cord...

Control Of Central Nervous System Iron

The brain has specific requirements that demand exacting control of iron (29,30). Not only is iron required for the usual metabolic needs, such as adenosine tripho-sphate formation and ribonucleotide synthesis, but within the brain iron also subserves myelin formation, synaptic regulation, and neurotransmission. Furthermore, iron distribution is highly heterogeneous and is highest in the cerebellum and midbrain. This distribution, however, is not apparent at birth and tends to increase over...

Biochemical Determinants Of Sleep

The major neurotransmitter pathways that regulate the wakefulness system are the ascending reticular activating systems (ARAS). Projecting to the thalamus, hypothalamus, and basal forebrain, the ARAS includes cholinergic, noradrenergic, dopaminergic, and histaminergic neurons. Within the laterodorsal and PPT tegmental nuclei at the pontomesencephalic junction, cholinergic neurons project to the thalamus, posterior hypothalamus, and basal forebrain region. These cholin-ergic neurons fire at...

Circadian Pattern Of Restless Legs Syndromeperiodic Limb Movements

RLS symptoms are ''worst during the evening and or night hours.'' Although the circadian physiology of RLS had not been yet scientifically demonstrated when the above statement was first made, it had already appeared as the fourth decisive item in the (1995) diagnostic criteria for RLS (89). This is because the daily rhythm of RLS has always been one of the most solid and undisputed empiric feature of RLS. The oldest dated RLS description, made by Willis in 1683, already underlined the temporal...

Dietary Forms of Iron

Iron occurs in two fundamental forms in the human diet heme and nonheme iron (2). Heme iron refers to all forms of iron from plant and animal sources, in which the iron molecule is tightly bound within the porphyrin ring structure as is found in both myoglobin and hemoglobin. Nonheme iron refers to all other forms of iron. Contaminant iron that is derived from dust and soil iron is relatively unavailable to the absorptive cells, but may constitute a significant amount of iron intake in...

Circadian And Homeostatic Control Of Sleep

Sleep, as feeding and locomotor activity, strictly follows a circadian expression (68,69). In humans, sleep occurs during dark, together with high levels of circulating MLT and low values of body temperature (70). Circadian organization of sleep depends on the internal SCN drive and external factors mainly represented by light. Exogenous entrainments exert a so-called masking effect on endogenous rhythm, so sleep timing is the natural consequence of a harmonic fight between geophysical and...

Cortex

In the cortex, somatosensory stimuli are ultimately processed and voluntary movement activity is mediated. As mentioned above, SEP were basically normal in RLS patients (21), however, the sensory cortex has not otherwise received any systematic attention. There is only one study exploring cortical activity in RLS patients during a three-minute vigilance EEG (130). In comparison to control subjects, RLS patients showed an increased delta and fast alpha power, while slow alpha was decreased. The...

Dopamine D3 Receptor Knockout D3ko Mice Model

Mammalian nervous system activity is under strong circadian control from the hypothalamic suprachiasmatic nuclei (SCN) (25,26). One SCN projection is to the dorsomedial hypothalamic (A11) dopaminergic nucleus (27,28). A11 neurons are the major source of spinal dopamine, with strong projections to the sympathetic preganglionic neurons in the intermediolateral nucleus (13,28). Spinal cord function is strongly modulated by monoamines (serotonin, dopamine, and nora-drenalin) however, there are only...

Input to Pineal Gland and Sites of Action of Melatonin

The foremost neuronal input to PG consists of a multisynaptic pathway named the retinohypotalamic-pineal tract. The first step of this pathway is represented by the previously mentioned RHT, which comes from the retina and ends in the ventrolateral SCN (55,56). The endogenous pacemaker (SCN) projects inhibitory and excitatory neurons to the PVN mediated by GABA and VIP VP, respectively (57). The PVN projects to the intermediolateral neurons of the first three cervical spinal levels via oxytocin...

Iatrogenic Restless Legs Syndrome 255

Winkelman Introduction . . . . 255 Antidepressants 256 Histamine-Receptor Antagonists 260 23. Other Restless Legs Syndrome Associations 269 Irfan Lalani and William G. Ondo Introduction 269 Rheumatological Disorders 269 Ataxia 270 Tremor 271 Tourette's Syndrome 271 Multiple Sclerosis . . . . 272 Sleep Apnea . . . . 272 Miscellaneous Associations 273 Conclusion . . . . 273 References 273 Section IV Treatment of Restless Legs Syndrome 24. Treatment Overview 275 Scales...

Iron Losses

The low solubility of iron at physiologic pH precludes urinary excretion as a major mechanism of maintaining iron homeostasis. Thus, in contrast to most other trace minerals whose homeostasis in maintained by excretion, the primary mechanism of maintaining whole body iron homeostasis is to regulate the amount of iron absorbed so that it approximates iron losses. Iron losses can vary considerably with the gender of the individual. In male humans, total iron losses from the body have been...

Entrainment Effect of Motor Activity and Sleep

The second and the third standard diagnostic criteria state that RLS symptoms ''begin or worsen during rest or inactivity, and are partially or totally relieved by movement'' (99). Experiments using SIT demonstrated that this assumption is valid also for PLM which, as with the sensation discomfort, increase linearly with rest (100). Such evidences suggested that the evening and night worsening of RLS severity was due to a generic and physiological decrease of locomotor activity during the late...

Reflexes and the Spinal Cord

PLM have been thought to be highly stereotyped movements, possibly resembling the Babinski sign (91) or the flexor reflex (92) and could thus be the consequence of a transitory loss of supraspinal inhibitory influences on descending motor pathway function. Another line of research has explored segmentally localized reflexes in RLS patients, especially the H-reflex, in search for a spinal hyperexcitability. PLMS have been likened to the Babinski sign (91,93), which in healthy persons is absent...

Occurrence of Restless Legs Syndrome

Sleep Disorders Center, Avesta Hospital, Avesta, Sweden Bjarn Bjorvatn Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway Epidemiology is the study of the distribution and determinants of diseases, health-related states, or events in a specified population (Epi ''on, upon, among'' Demos ''the people, population, man'' Ology ''the study of''). Evaluations of distributions of a disease may include the investigation of geographical distributions. In...

Melatonin

Before its molecular structure and its multiple roles were deciphered, melatonin (MLT) was merely a mysterious substance produced by the pineal gland (PG). It became an object of interest because of its control of skin coloration on amphibians. In 1917, McCord and Allen, applying extract of bovine PG to frog skin, produced a skin lightening (38). This extract was later (1958) identified to be N-acetyl-5-meth-oxytryptamine, and named by their discoverers Lerner et al. as MLT because of its...

Role of Dopamine and Melatonin in RLS Circadian Expression

Some evidence supports the idea that dopamine hypofunctioning plays an important role in RLS pathogenesis symptoms improve by dopaminergic drugs and worsen with antidopaminergic drugs. PLM and RLS are often noticed in patients affected by Parkinson's disease. Motor hyperexcitability in animal models has been induced by lesions of the hypothalamic dopaminergic neurons that project to spinal centers. Iron deficiency (iron is a key coenzyme in the dopamine anabolism) is a strong risk factor for...

Sleep Disorders Classification

The Association of Sleep Disorders Centers initially classified sleep-wake disorders into four categories, including disorders of initiating and maintaining sleep disorders of excessive somnolence disorders of sleep-wake schedule and dysfunctions associated with sleep, sleep stages, or partial arousals. In 1990, the ICSD described a system, which was slightly revised in 1997, that divided the 84 sleep disorders into four classes dyssomnias, parasomnias, sleep disorders associated with medical...

Restless Legs Syndrome Diagnostic Criteria and Differential Diagnosis

Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Singapore, Republic of Singapore Restless legs syndrome (RLS) is characterized by an urge to move the limbs, associated with unpleasant sensations deep inside the legs and sometimes the arms (1). RLS, first named in 1945 by the Swedish neurologist Ekbom (2), has a prevalence of about 5 to 15 in the White population (3,4), but is less common amongst Asians (5). In 1995, the International RLS Study Group...

Definition of RLS and PLMs Circadianity

Unfortunately, there are no biological markers for objectively assessing the daily RLS course. The only objective measure available for this topic may be represented by the periodic limb movements (PLM) index. Therefore, in order to obtain reliable and comparable data, investigators first of all should decide which parameter to observe, and then to monitor its trend by the same standard methods and in the same standard environmental conditions. Sensory RLS symptoms could be assessed only...

References

Polydefkis M, Allen RP, Hauer P, et al. Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 2000 55 1115-1121. 2. Wetter TC, Stiasny K, Winkelmann J, et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999 52 944-950. 3. Montplaisir J, Michaud M, Denesle R, et al. Periodic leg movements are not more prevalent in insomnia or hypersomnia but are specifically associated with sleep disorders involving a dopaminergic...

Heme Iron Absorption

Heme iron is soluble in an alkaline environment hence, no binding proteins are necessary for its luminal absorption. Specific transporters exist for heme on the surface of enterocytes and efforts are being made to characterize this heme transporter (5,6). After binding to its receptor, the heme molecule is then internalized and acted upon by heme oxygenase (HOX1) to release the iron to the soluble cytoplasmic pool (7). HOX1 is not induced by oral administration of hemoglobin (a source of heme)...

Nonheme Iron Absorption

Divalent metal transporter (DMT) is a transmembrane protein that resides on the luminal membrane and has a strong preference for divalent metals. It exists in several isoforms (DMT1 and DMT2) (2,9). The nonheme iron in the lumen of the gut has variable solubility, depending on the various amounts of ferric and ferrous iron and the amount of iron-binding compounds. The rapid conversion of ferric to ferrous iron is accomplished by a membrane-bound member of the cytochrome P450 family, Dcytb,...

Common and Scientific Name

Iron is element number 26 in the periodic table and has an atomic weight of 55.85. It is the fourth most abundant element and the second most abundant metal in the earth's crust. In simple aqueous solutions, iron exists in two principal oxidation states ferrous (Fe2+) and ferric (Fe3+). The two forms of iron in solution are interchanged by the addition or subtraction of an electron. Many common reducing agents (e.g., ascorbic acid) will convert ferric iron to ferrous iron, while simple exposure...

History of Restless Legs Syndrome

Department of Neurology, UMDNJ-RW Johnson Medical School, New Brunswick, New Jersey, U.S.A. EARLY DESCRIPTIONS OF CONDITIONS RESEMBLING RESTLESS LEGS SYNDROME When was the first description of restless legs syndrome (RLS) Montaigne, the great French essayist, wrote about restlessness of the legs, sometimes aroused by sermons in church, ''so that though I was seated, I was never settled'' (1). Montaigne seems to catch the core feeling of RLS the ''never settled.'' Montaigne wrote that, ''it may...

Genetics of Restless Legs Syndrome

Department of Molecular Cardiology, Lerner Research Institute, Centers for Cardiovascular Genetics and Molecular Genetics, The Cleveland Clinic Foundation, and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, U.S.A. Max Planck Institute of Psychiatry, RG Neurological Genetics, Institute of Human Genetics, Munich, Germany Department of Molecular Cardiology, Lerner Research Institute, Centers for Cardiovascular...

Approaches to Preventative Iron Supplementation

One of the great concerns regarding iron deficiency anemia is the adequacy of iron intake during periods of high iron losses. This has led to a reevaluation of the concept of ''daily iron supplements'' (38,39). At issue is the relative effectiveness of daily therapeutic doses of iron compared to the administration of lower ''prevent-ative intermittent iron'' doses. The concept is this because the GI enterocyte will FIGURE 1 Putative mechanism for the absorption of iron in enterocytes of the...

Consequences of Sleep Deprivation

Department of Neurology, Sleep Disorders Unit, Singapore General Hospital, National Neuroscience Institute, Singapore, Republic of Singapore Department of Neurology, Sleep Disorders Center, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. With the invention of the light bulb and ready availability of electrical power, sleep loss has become increasingly prevalent in industrialized nations. Air travel across multiple time zones, globalization of commercial markets, shift work, 24 7 services,...

What Is The Role Of Peripheral Neuropathy In Restless Legs Syndrome

Peripheral neuropathy is an assumed cause of secondary RLS and reviewed in detail in Chapter 19. It is thought that at the basic perceptual level sensory stimuli are distorted, possibly leading to a hypersensitization of the sensory pathway that may induce a circulus vitiosus maintaining restless legs symptoms. Peripheral neuropathy can be evoked by a broad range of medical diseases, toxins, and drugs. The overall prevalence is about 2 to 4 , and in persons older than 55 years rises to about 8...

Contributors

Allen Department of Neurology, Johns Hopkins University, Baltimore, Maryland, U.S.A. John Beard Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, U.S.A. Philip M. Becker Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, U.S.A. Georgianna Bell Restless Legs Syndrome Foundation, Rochester, Minnesota, U.S.A. Bjarn Bjorvatn Department of Public Health and Primary Health Care, University of...

Ohdalesioned And Irondeficient Mice

In Qu et al.'s anatomical study (16), fluorescent tracer Fluoro-Gold (FG) was used to investigate the pathway of diencephalic dopaminergic innervation of the spinal cord in mice. The fluorescent tracer FG was stereotaxically injected into the lumbar spinal cord of C57BL mice. Then, the diencephalic sections were stained with TH antibodies and the FG tracer present in the diencephalic dopaminergic neurons were examined under fluorescence microscope. The results suggested that the diencephalic...

Suprachiasmatic Nucleus

The existence of an endogenous pacemaker has been strengthened by more recent experiments conducted on humans and animals in free-running conditions. One study protocol showed that the main circadian rhythms temperature, sleep, and hormone secretion also persist in experimental isolation from all the exogenous entrainments, including light 18 . Under constant external environmental conditions, the persistent biological rhythm of the majority of living beings has a period not exactly of 24...

Introduction

Restless legs syndrome RLS is a common disease with a prevalence up to 10 in the general population 1,2 . The age of onset is variable, tending to be earlier in familial RLS, and it affects women somewhat more than men. This syndrome is a sensomotor disorder characterized by an intense urge to move the limbs, especially the legs. Some patients report an actual sensation whereas others only report the uncontrollable need or urge to move, referred to as an akathisia. This distinguishes it from...

Ontogeny Of Sleep

Newborns can spend greater than 16 hours per day sleeping approximately 50 of their total sleep time is composed of REM sleep. In fact, when newborns first fall asleep, they immediately enter REM sleep, also known as active sleep. Restless movements of the facial muscles, arms, and legs occur during active sleep it can be difficult to distinguish wakefulness from REM sleep on PSG. There is a gradual change from the infant's multiphasic sleep to the adult's...