Restless Leg Syndrome Flashcards
What is restless leg syndrome? 5
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
What criteria support a RLS diagnosis? 3
1) positive family history of RLS 2) positive response to dopaminergic treatment 3) Presence of periodic limb movements
What can complicate an RLS diagnosis? 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.
What are the two RLS phenotypes ? 2
Primary and idiopathic/secondary RLS
Describe the phenotype of RLS. 3
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
What causes secondaryRLS?3
Usually a condition that results in iron deficiency e.g.: 1) Iron deficient anemia 2) Pregnancy 3) Renal failure
What is a periodic limb movement? 2
Involuntary repetitive leg movement and with primarily extension of the big toe and dorsiflexion of the ankle
What does a babinski imply and what is the importance in RLS? 5
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.
What are the PLM criteria? 4
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.
How many PLM/H are required for it to be considered pathological?
5
What are consequences of PLMs? 2
Cortical arousal and autonomic arousal —> tachycardia and increased BP.
What other sleep disorders are PLMs associated with? 5
1) Sleep apnea 2) Rapid eye movement sleep behavior disorder 3) Insomnia 4) hypersomina 5) narcolepsy
What non-sleep related disorders are associated with PLMs?
1) Congestive HF 2) Spinal cord injury 3) End stage renal failure 4) Hypertension
Can healthy people experience PLMS?
Yes, between 30- 50% of people over the age of 60 have a PLM index of more than 5/h
What is the clinical significance of RLS and PLM?
1) Delays in sleep onset, sleep disruption and decreased sleep efficiency 2) CVD risk 3) Excessive daytime sleepiness 4) Depression and pain
What can sleep deprivation result in? 8
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
What are the four main theories regarding the pathophysiology of RLS?
1) Genetic abnormalities 2) Disorders of iron metabolism 3) Dopaminergic dysfunction 4) Central opiate system dysfunction
Describe the possible aetiology of RLS? 5
1) insufficient brain iron 2) impaired dopaminergic brain function 3) Spinal hyperexcitabilty 4) Spontaneous sensations and movements 5) RLS and PLMs
What genetic factors are implicated in RLS? 2
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.
What is the most accurate measure of overall iron status in the body? And why? 3
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.
What evidence is there for iron deficiency in RLS? 3
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.
What is dopamine? 2
Dopamine is catecholamine neurotransmitter that binds to D1 like and D2 like receptors.
What is the difference between D1 like receptors and D2 like receptors? 2
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.
What are the physiological functions of dopamine? 6
1) In the CNS: behavior cognition, voluntary movement, sleep, mood and learning 2) Nigrostriatal system: motor control 3) Mesocortical system: reward behavior and addiction
Describe Parkinson’s Disease: 5
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)
What are the differences between RLS and PD? 5
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.
What are the basal ganglia and how do they function? 4
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
What can disorders of the basal ganglia result in?
1) Hyperkinesia 2) Hypokinesia
What structures make up the basal ganglia? 7
1) Striatum 2) Caudate nucleus 3) Putamen 4) Globus allidus interna and externa 5) Subthalamic nucleus 6) Substantia nigra
Describe the striatum: 3
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.
What is the striatal receptor binding potential? 2
It is a combined measure of the density of available neuroreceptors and the affinity of a drug to that neuroreceptors.
What is DAT and what is its function? 3
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.
Explain the role iron plays in dopamine synthesis. 2
Iron is a cofactor for tyrosine hydroxylase, which is an enzyme that converts tyrosine into L-dopa which is the precursor for dopamine.
Describe the A11 diencephalospinal dopaminergic pathway: 4
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.
Explain how dysfunction of the A11 diencephalospinal dopaminergic pathway may result in the painful stimuli seen in RLS patients. 3
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.
Explain how RLS is associated with CVD: 6
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.
What metabolic changes are associated with PLM and Sleep-deprivation? And how does this result in CVD? 4
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.
Explain the hypothetical pathway of spinal cord positive feedback mechanism mediating dopamine response in RLS 3
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
There are 2 A11 pathways hypotheses, briefly discuss them 6
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
What is the evidence for dopamine dysfunction in RLS? 3
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.
Some RLS patients describe their symptoms as painful, can you give a physiological reason for this?
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
What is the difference between allodynia and hyperalgesia?
Allodynia is the increased sensitivity to non-noxious stimuli where as hyperalgesia is an increased sensitivity to pain
What are the possible treatment options for RLS patients?
1) Dopaminergic system 2) Iron 3) Opioid system 4) GABAergic system
Explain the mechanism of alpha-2-delta ligands
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.
Explain the use of GABAergic system drugs
These anticonvulsants are the primary CNS inhibitory neurotransmitter and thus decrease neuronal excitability.
What is augmentations? 5
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
What are the risk factors for developing augmentation?
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.
