Restless Leg Syndrome

Question 1

What is restless leg syndrome? 5

Answer 1

It is a sensorimotor disorder that results in an urge to move due to unpleasant sensations that is relieved by movement. It is exacerbated by inactivity and is worse in the evening. These symptoms cannot be accounted for by any alternative diagnosis

Question 2

What criteria support a RLS diagnosis? 3

Answer 2

1) positive family history of RLS 2) positive response to dopaminergic treatment 3) Presence of periodic limb movements

Question 3

What can complicate an RLS diagnosis? 3

Answer 3

1) People have various descriptions of what they are feeling? E.g. being stung by 20 mosquitoes, my leg is like a candy cane slowly being eaten from the inside out. 2) Various phenotypes 3) Many conditions mimic RLS.

Question 4

What are the two RLS phenotypes ? 2

Answer 4

Primary and idiopathic/secondary RLS

Question 5

Describe the phenotype of RLS. 3

Answer 5

1) Can have an early or late onset 2) can be familial or sporadic, however 60-65% of RLS cases indicate a positive family history 3) the 2:1 female preponderance

Question 6

What causes secondaryRLS?3

Answer 6

Usually a condition that results in iron deficiency e.g.: 1) Iron deficient anemia 2) Pregnancy 3) Renal failure

Question 7

What is a periodic limb movement? 2

Answer 7

Involuntary repetitive leg movement and with primarily extension of the big toe and dorsiflexion of the ankle

Question 8

What does a babinski imply and what is the importance in RLS? 5

Answer 8

RLS patients often present with PLM, characterized by extension of the big toe and dorsiflexion of the ankle, this is similar to the Babinski sign found in patients with UMN lesions. This suggests that the spinal cord is isolated from inhibitory control resulting in spinal hyperexcitability.

Question 9

What are the PLM criteria? 4

Answer 9

1) EMG amplitude that increases by 8uv above baseline. 2) Each individual burst last for between 0.5 to 10 seconds. 3) Each EMG must be separated by at least 5 but not more than 90 seconds. 4) There must be at least 4 EMG burst.

Question 10

How many PLM/H are required for it to be considered pathological?

Answer 10

5

Question 11

What are consequences of PLMs? 2

Answer 11

Cortical arousal and autonomic arousal —> tachycardia and increased BP.

Question 12

What other sleep disorders are PLMs associated with? 5

Answer 12

1) Sleep apnea 2) Rapid eye movement sleep behavior disorder 3) Insomnia 4) hypersomina 5) narcolepsy

Question 13

What non-sleep related disorders are associated with PLMs?

Answer 13

1) Congestive HF 2) Spinal cord injury 3) End stage renal failure 4) Hypertension

Question 14

Can healthy people experience PLMS?

Answer 14

Yes, between 30- 50% of people over the age of 60 have a PLM index of more than 5/h

Question 15

What is the clinical significance of RLS and PLM?

Answer 15

1) Delays in sleep onset, sleep disruption and decreased sleep efficiency 2) CVD risk 3) Excessive daytime sleepiness 4) Depression and pain

Question 16

What can sleep deprivation result in? 8

Answer 16

1) decreased survival 2) increased pain 3) Impaired memory and concentration 4) Poor focus and attention 5) Slower reaction times 6) Greater utilization of healthcare 7) More frequent MVA and work place errors 8) Heightened inflammation and risk of disease

Question 17

What are the four main theories regarding the pathophysiology of RLS?

Answer 17

1) Genetic abnormalities 2) Disorders of iron metabolism 3) Dopaminergic dysfunction 4) Central opiate system dysfunction

Question 18

Describe the possible aetiology of RLS? 5

Answer 18

1) insufficient brain iron 2) impaired dopaminergic brain function 3) Spinal hyperexcitabilty 4) Spontaneous sensations and movements 5) RLS and PLMs

Question 19

What genetic factors are implicated in RLS? 2

Answer 19

1) MEIS1 has been identified as the strongest genetic risk factor for developing RLS. It is important in the embryonic development of the limbs, heart and eye development.

Question 20

What is the most accurate measure of overall iron status in the body? And why? 3

Answer 20

1) Ferritin and transferrin as iron binds to these proteins to facilitate transport and storage in a non-reactive form. 2) Ferritin is the best serum marker of iron stores. 3) Transferrin is responsible for transporting iron from storage sites to other site in the body.

Question 21

What evidence is there for iron deficiency in RLS? 3

Answer 21

1) Disorders associated with an iron deficiency have a high prevalence of RLS. 2) Treating the underlying iron deficiency leads to improved symptoms 3) It has been shown that there is impaired iron metabolism and decreased iron concentrations in the substantia nigra and putamen in RLS patients.

Question 22

What is dopamine? 2

Answer 22

Dopamine is catecholamine neurotransmitter that binds to D1 like and D2 like receptors.

Question 23

What is the difference between D1 like receptors and D2 like receptors? 2

Answer 23

Activation of D1 like receptors results in an increase in cAMP causing excitation, whereas binding to D2 like receptors results in a decrease in cAMP resulting in an inhibitory effect.

Question 24

What are the physiological functions of dopamine? 6

Answer 24

1) In the CNS: behavior cognition, voluntary movement, sleep, mood and learning 2) Nigrostriatal system: motor control 3) Mesocortical system: reward behavior and addiction

Question 25

Describe Parkinson’s Disease: 5

Answer 25

PD is a neurodegenerative disorder characterized by a resting tremor, rightly, bradykinesia, gait disturbance and postural instability. This results from degeneration of the dopaminergic neurons in the substantia nigra (basal ganglia)

Question 26

What are the differences between RLS and PD? 5

Answer 26

1) RLS is more prevalent than PD 2) Iron deficiency in RLS whereas there is increased iron in PD 3) no evidence of substance nigra neuron degeneration in RLS 4) RLS a distinct genetic component 5) Other therapeutic age nets act differently.

Question 27

What are the basal ganglia and how do they function? 4

Answer 27

1) Grey matter masses in the cerebrum that function to: 2) control and regulate the activity of the motor and pre-motor cortical areas so that voluntary movement can be performed 3) Muscle tone inhibition 4) Co-ordinates sustained muscle contraction such as posture

Question 28

What can disorders of the basal ganglia result in?

Answer 28

1) Hyperkinesia 2) Hypokinesia

Question 29

What structures make up the basal ganglia? 7

Answer 29

1) Striatum 2) Caudate nucleus 3) Putamen 4) Globus allidus interna and externa 5) Subthalamic nucleus 6) Substantia nigra

Question 30

Describe the striatum: 3

Answer 30

It is a component of the motor system that receives glutamatergic and dopaminergic inputs. It’s the primary input to the rest of the basal ganglia.

Question 31

What is the striatal receptor binding potential? 2

Answer 31

It is a combined measure of the density of available neuroreceptors and the affinity of a drug to that neuroreceptors.

Question 32

What is DAT and what is its function? 3

Answer 32

DAT is a dopamine transporter and it functions in the reuptake of dopamine from the synapse. Therefore, a decrease in DAT would result in increased extracellular dopamine concentrations.

Question 33

Explain the role iron plays in dopamine synthesis. 2

Answer 33

Iron is a cofactor for tyrosine hydroxylase, which is an enzyme that converts tyrosine into L-dopa which is the precursor for dopamine.

Question 34

Describe the A11 diencephalospinal dopaminergic pathway: 4

Answer 34

The only significant dopamine pathway. It is anatomically connected to the suprachiasmatic nucleus which is involved with the control of circadian rhythms. It is further involved in the sensorimotor integration and anti-nociception at the level of the spinal cord.

Question 35

Explain how dysfunction of the A11 diencephalospinal dopaminergic pathway may result in the painful stimuli seen in RLS patients. 3

Answer 35

The A11 dopaminergic cells are involved in pain control (dopamine inhibit the neurons in the dorsal horn where pain information is recieved). Therefore, dysfunction may result in gate dysfunction for this pathway allowing painful stimuli through.

Question 36

Explain how RLS is associated with CVD: 6

Answer 36

RLS results in PLM related sleep fragmentation and sleep deprivation. Both sleep deprivation and PLM related sleep fragmentation are associated 1) Metabolic, 2) Neural and 3) Vascular changes. These changes can result in vascular injury and/or hypertension which increases the risk of CVD.

Question 37

What metabolic changes are associated with PLM and Sleep-deprivation? And how does this result in CVD? 4

Answer 37

Both SD and PLMRSF can result in glucose intolerance, insulin sensitivity and diabetes all of which can result in vascular injury. Furthermore, there may be production of ROS causing vascular injury.

Question 38

Explain the hypothetical pathway of spinal cord positive feedback mechanism mediating dopamine response in RLS 3

Answer 38

1) DA inhibit pre-ganglion is sympathetics and thus in its absence, basal sympathetic tone may increase. 2) Increased adrenaline via inner action of skeletal muscle, in turn, might irritate muscle spindles. 3) This resulting enhanced input from pain-encoding high threshold muscle affronts are insufficiently suppressed in the absence of D2 like receptors

Question 39

There are 2 A11 pathways hypotheses, briefly discuss them 6

Answer 39

Hypothesis 1: The A11 pathway modulates sympathetic output to the muscles. Therefore, hypofunction of this pathway results in an increased sympathetic outflow to the periphery changing the sensory information returned to the spinal cord. Hypothesis 2: The peripheral sensory output is altered at the level of the spinal cord. The A11 pathway modulates sensory input to the dorsal horn. A decreased in dopamine would result in abnormal sensory information reaching the thalamus

Question 40

What is the evidence for dopamine dysfunction in RLS? 3

Answer 40

1) Patients show a positive response to dopamine treatment. 2) PAtients have altered CSF levels of dopamine, metabolites and regulatory factors 3) Neuroimaging studies have shown striatal dopamine dysfunction.

Question 41

Some RLS patients describe their symptoms as painful, can you give a physiological reason for this?

Answer 41

RLS patients have amplified nociceptive processing and increased pain sensitivity because of central sensitization. This is a process of increased neuronal membrane excitiabiliy and decreased neuronal inhibition. This results in a decreased stimulation threshold leading to increased output of action potentials

Question 42

What is the difference between allodynia and hyperalgesia?

Answer 42

Allodynia is the increased sensitivity to non-noxious stimuli where as hyperalgesia is an increased sensitivity to pain

Question 43

What are the possible treatment options for RLS patients?

Answer 43

1) Dopaminergic system 2) Iron 3) Opioid system 4) GABAergic system

Question 44

Explain the mechanism of alpha-2-delta ligands

Answer 44

These ligands act by binding to the alpha 2 delta subunits of voltage-activated calcium channels and decreasing the influx of calcium. A decrease in calcium, decreases the release of excitatory neurotransmitters, from the presynaptic terminals with subsequent decrease in post-synaptic excitability.

Question 45

Explain the use of GABAergic system drugs

Answer 45

These anticonvulsants are the primary CNS inhibitory neurotransmitter and thus decrease neuronal excitability.

Question 46

What is augmentations? 5

Answer 46

It is a response to dopaminergic treatment whereby symptoms: 1) appear earlier in the day 2) tend beyond the limbs 3) have a more rapid onset at rest 4) have increased severity 5) are relived by medication for shorter duration

Question 47

What are the risk factors for developing augmentation?

Answer 47

1) Greater severity of symptoms pre-treatment ) comorbid asthma’ 3) older age 4) longer treatment duration 5) positive family history of RLS 6) decreased serum ferritin levels.

Question 48