Overview:


Legs
Figure 1 http://ionmyhealth.com/blog/the-link-between-sleep-apnea-and-restless-leg-syndrome/#
Restless Leg Syndrome (RLS), also referred to as Willis-Ekbom disease, is a sensorimotor disorder characterized by an irresistible urge to move the legs or other body parts, such as the head and arms. This urge is caused by uncomfortable or even painful sensations deep within the affected body parts. It is estimated that about 10% of adults worldwide are afflict by RLS (Ryan, Slevin, 2006). Women appear to be more susceptible than men and this prevalence increases with age (Hening, Allen, Tenzer, Winkelman, 2007).

This page presents what is known about RLS and its underlying neurological causes as well as postulates a few hypotheses as there is still so much to learn on the topic.

Signs and Symptoms:


It is often difficult for patients with RLS to adequately describe their symptoms as descriptions for the uncomfortable sensations vary. In order to aid in the description and diagnosis of RLS, a review and revision of the diagnostic criteria and associated features was made. The following are the four primary features defining RLS. 1) The urge to move the legs, usually associated with dysethesias. As mentioned earlier the compulsion to move is often accompanied by uncomfortable or painful sensations and not always limited to the legs. 2) Onset or exacerbation with rest. The uncomfortable sensations generally worsen during inactivty or when in the person is sitting or lying down. The more restful the position or the longer the duration the more likely that symptoms will occur. 3) Relief with movement. Symptoms are partially or totally relieved by activity for as long as the activity persists. 4) Circadian pattern. Symptoms are worse or only present during the evening or at night. (Hening, Allen, Tenzer, Winkelman, 2007). A summary of diagnostic criteria for RLS is given under the Helpful Links section. Some additional symptoms not necessary for diagnosis but common nonetheless are 1) a positive family history of RLS, 2) initial responsiveness to dopaminergic treatements, 3) presence of periodic leg movements (PLM) and 4) generally an unremarkable neurological examination (Manconi, Hutchins, Feroah, Zucconi, Ferini-Strambi, 2007). As of yet there are no objective biological identifying markers for RLS and so diagnosis is based on standard clinical criteria.

Two Forms:


RLS can be primary, idiopathic, and independent of any other disease or secondary, in which RLS symptoms are caused by another condition both neurologic and non-neuerologic in origin (Thomas, Watson, 2008). There are many diverse underlying conditions associated with RLS, however, the focus of this page is on the neurologic sources. It is believed that the secondary conditions cause symptoms of RLS are because they induce iron deficient states. Explanations for the iron deficiency connection to the mechanisms of RLS are further discussed in the subsequent sections. Although of possible different origins, both the primary and secondary forms may share the same pathogenetic mechanism due to a dysfunction of the dopaminergic system (Manconi, Hutchins, Feroah, Zucconi, Ferini-Strambi, 2007).

Pathogenic Hypothesis:


Much is yet to be determined regarding the aetipathogenesis and underlying mechanisms of this prevalent syndrome. Hopefully this section will shed some light on the established hypothesis as well as areas requiring further study.

neural loop 2.png
Figure 2. ProposProposed neuronal loop involving the cerebellum, thalamus, red nucleus and inferior olive, which is believed to be responsible for the sensorimotor symptoms of restless legs syndrome. (Winkleman, 2006)

The jury is still out as to whether the role agents play in RLS is to act on the nigrostriatal or midbrain perihypothalamic dopaminergic systems or at the spinal cord level to modulate sensorimotor disturbance, or both (Thomas, Watson, 2008). Either way, the dopaminergic system is involved. The conclusion for the involvement of the dopaminergic system is based on a few lines of evidence. One is that there is activation of the subcortical regions such as the cerebellum, thalamus, red nucleus and inferior olive during involuntary leg movements in RLS and no activation in cortical regions, suggesting that it is subcortically based (Winkleman, 2006). Second is that RLS symptoms are augmented by dopamine antagonists and reduced by dopamine agonists (Winkleman, 2006). This positive response to dopamine therapy supports the theory of dopaminergic system involvement. Also, it has been shown that there is abnormal dopamine receptor binding and transport in patients with RLS, however, these studies have yielded inconsistent results and therefore must be interpreted with caution (Winkleman, 2006). Lastly, RLS symptoms follow a circadian pattern with symptoms arising at night, which correspond to when dopamine levels are lowest (Thomas, Watson, 2008).

Dopaminergic System:
The Dopaminergic System is located in the Basal Ganglia and composed of three main pathways that transmit dopamine from one area of the brain to another. The A9 substantia nigra region is most relevant to RLS because this system is involved with voluntary movement (Winkleman, 2006). It is referred to as the nigrostriatal pathway because it beings in the substantia nigra (pars compacta) and ends in the striatum. This pathway modulates the direct and indirect motor loops in the basal ganglia. Direct pathway striatal neurons have D1 dopamine receptors, which depolarize the cell in response to dopamine. In contrast, indirect pathway striatal neurons have D2 dopamine receptors, which hyperpolarize the cell in response to dopamine. The nigrostriatal pathway thus has the dual effect of exciting the direct pathway while simultaneously inhibiting the indirect pathway (Knierim, 2013).

Pathways.png
Figure 3 Direct and Indirect Pathways

Additional Hypotheses:


Other potential relationships between RLS and various anatomical regions have been studied. "The resemblance between PLM and the pain planatar reflex suggests a possible spinal cord hyperexcitability of the motor outflow" (Manconi, Hutchins, Feroah, Zucconi, Ferini-Strambi, 2007). The Aetiopathogenesis of Restless Legs article agrees that "results suggest that RLS pathology involves increased spinal cord excitability" (Zucconi, Manconi, Ferini-Strambi 2007). Abnormal somatosensory processing along with enhanced spinal cord excitability also appears to contribute to RLS. In patients with idiopathic forms of RLS temperature perception is altered and the nociceptive system effectiveness responds to analgesic substances in RLS therapy (Zucconi, Manconi, Ferini-Strambi, 2007). This is understandable considering the primary somatosensory cortex projects to the striatum of the nigrostriatal pathway. More on afferents and efferents discussed next.

Inputs and Outputs:


inputs
Figure 4 From a powerpoint slide on Blackboard

The striatum, composed of the caudate and putamen (See Figure 4), is the main recipient of afferent axons to the Basal Ganglia. It receives excitatory input from intralaminar nuclei of the thalamus as well as the entire cerebral cortex. Although the cortex is not active during involuntary leg movements of RLS, the somatosensory cortex may contribute to the pathogenesis of the disorder so it is important to note that the efferents from the primary somatosensory cortex project mainly to the putamen.


The globus pallidus internal segment (GPi) and the substantia nigra pars compacta (SNr) are the major outputs of the Basal Ganglia. Both make GABAergic inhibitory connections to respective targets as is diagrammed in Figure 3. The subthalamic nucleus is also a direct output target. Ansa lenticularis and lenticular fasiculus tracts carry projections from the GPi to many thalamic structures. Projections from the SNr travel to the superior colliculus. The loop that processes sensorimotor information from the somatosensory cortex projects to the ventral anterior and ventral lateral nuclei of the thalamus (knierim, 2013).


outputs 2.png
Figure 5


The nigrostriatal pathway has dopaminergic synapses onto the striatal neurons (Shown in Figure 3). It contains a mix of excitatory and inhibitory effects depending on the striatal neuron (Knierim, 2013).

Digging Deeper:


Dopamine is obviously a major player in the underlying mechanisms of RLS, however, there is still speculation as to its exact role. Nowadays many believe "a dysregulation, rather than a simple upregulation or downregulation of central dopaminergic neurotransmission, may underlie the pathogenesis of RLS" (Kim, Jhoo, Lee, Lee, Kim, Yoon, 2012). For example, a decrease in the release of dopamine may cause moderate to moderately severe RLS, but an increase in dopamine may cause severe RLS.

Directly connected to dopamine concentration is iron levels. As noted above, secondary RLS is a result of other conditions that are characterized by inadequate iron supplies. The main three are end-stage renal disease, pregnancy, and anemia. Iron is required for the synthesis of dopamine, which is a possible explanation for the role of iron in the pathophysiology of RLS (Thomas, Watson, 2008). Additionally, serum iron concentration decreases at night and therefore may be an underlying cause to the onset of symptoms in the evening. Small clinical studies have shown significant correlation between serum iron levels and RLS symptom severity (Winkleman, 2006).

Treatment Methods:

Treatment depends on factors including the severity of symptoms and the response to previous treatments. According to the review, Restless Leg Syndrome in Women, management of RLS divides patients into three groups: intermittent, daily, and refractory. For intermittent patients non-pharmacological methods should be implemented first. These include such things as iron replacement, mental-alerting activities, counter-sensory measures, exercise,and abstinence from caffeine, nicotine, and alcohol. Sometimes drug therapy, including dopamine agonists, levadopa, benzodiazepines, and low-potency opiods, is helpful. Daily patients typically use dopamine agonists, but it comes with its own adverse effects, which consist of rebound at the end of the dosing period and augmentation of symptoms. These effects are long-term and increase in severity. For patients experiencing refractory daily RLS, the first line of treatment is a dopaminergic, however, this is not always adequate and so the patient may need to switch to another class of drug or supplement with a different medication (Thomas, Watson, 2008).

Concluding Thoughts:


RLS can be accurately diagnosed through the four clinical features along with the patient's medical history during a regular physical examination and treatment plans can be implemented in an effort to suppress the symptoms. Despite its' prevalence, it remains underdiagnosed and undertreated. The knowledge of the underlying causes to RLS are lacking and so further research on the topic lies ahead. It is commonly accepted that the dopaminergic system is intimately associated with RLS, but not much is definite beyond that.

Glossary:


Dysethesia--"bad sensations" referring to pain or uncomfortable sensations
Idiopathic--arising spontaneously or from an obscure or unknown cause
Analgesic--(chiefly of a drug) acting to relieve pain
Dopamine--a neurotransmitter secreted by the substantia nigra pars compacta
Aetiopathogenesis--The cause and subsequent development of an abnormal condition or of a disease
GABAergic--a neuron that produces the inhibitory neurotransmitter GABA
Anemia--a condition marked by a deficiency of red blood cells or of hemoglobin in the blood, resulting in pallor and weariness
levadopa--a chemical that is the precursor to dopamine. It is a psychoactive drug used to treat Parkinson's Disease, RLS, etc.
low-potency opiods--any psychoactive chemical that resembles morphine or other opiates in its pharmacological effects but not as strong
benzodiazepines--any of a class of heterocyclic organic compounds used as tranquilizers

Helpful Links:


Essential, Supportive, and Associated diagnostic criteria for Restless Leg Syndrom:
Link

Restless Leg Syndrome Fact Sheet:
http://www.ninds.nih.gov/disorders/restless_legs/detail_restless_legs.htm

Homeopathic treatment for Restless Leg Syndrome:
Picture

Algorithm for treatment of Restless Leg Syndrome:
Chart

Quiz:


T/F:
1. RLS is not limited to the legs.
2. RLS can be diagnosed through biological markers specific to this disease.
3. There is a direct relationship between iron and dopamine levels.

Multiple Choice:
4. What is the pathway most relevant to RLS?
a. Mesocortical
b. Mesolimbic
c. Nigrostriatal
d. Tuberoinfunibular

5. What are the regions thought to be involved in RLS?
a. Cerebellar peduncles, pons, thalamus, abducens nuclei
b. Cerebellum, thalamus, inferior olive, red nucleus
c. Frontal eye fields, inferior olive, somatosensory cortex, dentate nuclus
d. Thalamus, primary motor cortex, pons, medulla

Short answer:
6. What are the two forms of RLS and how do they differ?
7. What are two of the regions that researchers believe the dopaminergic system is associated with RLS?
8. What are a few examples of non-pharmacological remedies for RLS?

References:


Hening, W., Allen, R. P., Tenzer, P., & Winkelman, J. W. (2007). Restless legs syndrome: Demographics, presentation, and differential diagnosis. (cover story). Geriatrics, 62(9), 26-29.

Kim, K. W., Jhoo, J. H., Lee, S. B., Lee, S. D., Kim, T. H., Kim, S. E., & ... Yoon, I. Y. (2012). Increased striatal dopamine transporter density in moderately severe old restless legs syndrome patients. European Journal Of Neurology, 19(9), 1213-1218. doi:10.1111/j.1468-1331.2012.03705.x

Knierim, James, Ph.D. "Basal Ganglia" (Chapter 4) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston. N.p., n.d. Web. 07 Dec. 2013. <http://neuroscience.uth.tmc.edu/s2/chapter14.html>.


Manconi, M. M., Hutchins, W. W., Feroah, T. R., Zucconi, M. M., & Ferini-Strambi, L. L. (2007). On the pathway of an animal model for restless legs syndrome.. Neurological Sciences, 28S53-S60. doi:10.1007/s10072-007-0738-8

Ryan, M., & Slevin, J. T. (2006). Restless legs syndrome. American Journal Of Health-System Pharmacy, 63(17), 1599-1612. doi:10.2146/ajhp060031

Thomas, K., & Watson, C. B. (2008). Restless Legs Syndrome in Women: A Review. Journal Of Women's Health (15409996), 17(5), 859-868. doi:10.1089/jwh.2007.0515

Winkelman, J. W. (2006). Considering the causes of RLS. European Journal Of Neurology, 138-14. doi:10.1111/j.1468-1331.2006.01586.x

Zucconi, M. M., Manconi, M. M., & Ferini Strambi, L. L. (2007). Aetiopathogenesis of restless legs syndrome. Neurological Sciences, 28S47-S52. doi:10.1007/s10072-007-0737-9

Quiz Answers:

1. T
2. F
3. T
4. C
5. B
6. Primary and Secondary. Primary forms origin are unknown (may be genetic) and secondary arise from different disorders such as renal failure, pregnancy and anemia.
7. Activation of subcortical regions and not subcortical regions, RLS symptoms are augmented by dopamine antagonists and reduced by dopamine agonists, abnormal dopamine receptor binding in RLS patients, when dopamine levels are reduced at night RLS symptoms worsen.
8. Iron replacement therapy, mental-alterting activities, counter-sensory measures, exercise, abstinence from caffeine, nicotine, and alcohol.