1. Sensory abnormalities in RLS: pain perception, gait problems, abnormal spinal reflexes - spinal excitability
Karin Stiasny-Kolster
Department of Neurology
Philipps University Marburg
Germany

2. Sensory symptoms in RLS
pulling
pins and needles
itching
prickling
throbbing
electric current
tearing
cramp-like
disagreeable sensation
aching
pain

3. The Symptoms Experienced by Sufferers
RLS symptoms reported to the physician
n = 1114
Paresthesias in the legs or other body
61.1
Sleep disturbed / interrupted / bad
60.6
Pain
59.4
Urge to move
55.3
Difficulties initiating sleep
48.1
Fatigue / Tiredness
43.4
The Symptoms Experienced by Sufferers
Participants in the research were asked to select symptoms from a list. They were asked to confirm all the symptoms they experience.
The symptoms recorded within REST Primary Care are consistent with those recorded within REST Population.
Difficulties maintaining sleep
39.2
Jerks / involuntary leg movements
37.0 %
Daytime sleepiness
32.2
Allen et al. Arch Intern Med 2005; 165:

4. Involvement of the sensory system in RLS?
Abnormalities in the peripheral or central sensory system?
Sensory loss?
Large fibers
Small fibers
Sensory gain?
Hyperalgesia, allodynia

5. Chronic pain Mixed pain Nociceptor pain Neuropathic pain
Pain after tissue injury with intact
peripheral and central
nociceptive structures
Neuropathic pain
Pain that results from damage of
central or peripheral nociceptive
structures
Mixed pain
e.g. inflammatory pain, arthralgia
e.g. sciatic pain syndrome, cancer pain
e.g. (Diabetic) neuropathy, trigeminal neualgia,
post stroke pain, spinal trauma,
infection, post herpetic neuralgia
parästhesias/dysästhesias
(burning, pins and needles, prickling)
(stabbing) pain
hyperalgesia
allodynia
- touch sensation 
pain sensation 
position sensation 
vibration sensation 
cold / warm 

6. Subclinical sensory neuropathy (Polydefkis et al. 2000)
Peripheral sensory system and RLS
Subclinical sensory neuropathy (Polydefkis et al. 2000)
Axonal neuropathy (Iannacone et al. 1995)
Cryoglobulinamic neuropathy (Gemignani et al. 1997)
Amyloid polyneuropathy (Salvi et al. 1990)
Charcot-Marie-Tooth neuropathy type 2 (Gemignani et al. 1999)

7. Prevalence of RLS in patients with polyneuropathy
5.2% RLS in (large-fiber) neuropathy (Rutkove et al. 1996)
30% (n=97) RLS in neuropathy patients (Gemignani et al. 2006)
- small-fiber neuropathy (52% in RLS+ vs. 24% in RLS -)

8. Chronic pain Mixed pain Nociceptor pain Neuropathic pain
Pain after tissue injury with intact
peripheral and central
nociceptive structures
Neuropathic pain
Pain that results after damage of
central or peripheral nociceptive
structures
Mixed pain
e.g. inflammatory pain, arthralgia
e.g. sciatic pain syndrome, cancer pain
e.g. (Diabetic) neuropathy, trigeminal neualgia,
post stroke pain, spinal trauma,
infection, post herpetic neuralgia
normal
Idiopathic RLS
???
parästhesias/dysästhesias
(burning, pins and needles, prickling)
(stabbing) pain
hyperalgesia
allodynia
- touch sensation 
pain sensation 
position sensation 
vibration sensation 
cold / warm 

9. Quantitative Sensory Testing (QST)*
Thermal detection and pain threshold (WDT, CDT, HPT, CPS, PHS)
- warm (C-warm-fiber); cold (A-cold-fiber)
- heat pain (C-nociceptors), cold pain (C- or A-nociceptors)
- paradoxical heat sensation during cold (C-nociceptors)
Mechanical detection threshold (MDT, A-low threshold mechanoreceptors, v. Frey hairs)
Mechanical pain threshold (MPT, A-fiber)
Mechanical pain sensitivity/MPS for pinprick (A-mechanonociceptors)
Mechanical pain sensitivity/MPS for light touch (A-low threshold mechanoreceptors)
Wind-up ratio (WUR, trains of single pinprick stimuli)
Vibration detection threshold (VDT) (A-fiber)
Pressure pain threshold (PPT, deep pain, deep (muscle) nociceptors)
TSA
* Protocol of the German Research Network on Neuropathic Pain

10. 1. Quantitative Sensory Testing (QST)* in RLS
Thermal detection and pain threshold (WDT, CDT, HPT, CPS, PHS)
- warm (C-warm-fiber); cold (A-cold-fiber)
- heat pain (C-nociceptors), cold pain (C- or A-nociceptors)
- paradoxical heat sensation during cold (C-nociceptors)
Mechanical detection threshold (MDT, A-low threshold mechanoreceptors, v. Frey hairs)
Mechanical pain threshold (MPT, A-fiber)
Mechanical pain sensitivity/MPS for pinprick (A-mechanonociceptors)
Mechanical pain sensitivity/MPS for light touch (A-low threshold mechanoreceptors)
Wind-up ratio (WUR, trains of single pinprick stimuli)
Vibration detection threshold (VDT) (A-fiber)
Pressure pain threshold (PPT, deep pain, deep (muscle) nociceptors)
* Protocol of the German Research Network on Neuropathic Pain

11. 1. Quantitative Sensory Testing (QST)* in RLS
Mechanical pain sensitivity to light
tactile stimuli
Mechanical pain sensitivity to pinprick
Pain rating
skale 0 < to 100
Force:
8, 16, 32, 64, 128, 256, 512 mN
Abnormal mechanical pain sensitivity?
Allodynia?
Hypalgesia/Hyperalgesia?
* Protocol of the German Research Network on Neuropathic Pain

12. Quantitative Sensory Testing (QST)* in RLS
* Protocol of the German Research Network on Neuropathic Pain
Study I
n (10 f / 1 m)
de novo iRLS %
Age (years) ± 10
Duration of RLS (years) ± 15
IRLS Score (1 – 40 points) ± 5
„Leg symptoms“ (1 – 100) ± 21
„Urge to move“ (1 – 100) ± 23
Stiasny-Kolster K, Magerl W, Oertel WH, Moeller JC, Treede RD Brain 127 (2004)

13. Mechanical hyperalgesia for pin-prick (n = 13)
hands
feet
lg pain ratings (VAS 0 – 100)
Lg pain ratings (VAS 0 – 100)
P  0.001
Mechanical hyperalgesia (5-fold): evening and morning, in feet and hands
No allodynia
Stiasny-Kolster et al. Brain 2004

14. Mechanical hyperalgesia for pin-prick (n = 13)
hands
feet
hands
feet
single evening dosage of L-DOPA improves
RLS but has no influence on pinprick ratings
(hyperalgesia)
long-term L-dopa treatment normalizes
hyperalgesia (- 70%)
Hyperalgesia
- in the evening and morning
- in hands and feet
no allodynia
Stiasny-Kolster et al. Brain 2004

15. II. Quantitative Sensory Testing (QST)* in RLS
Thermal detection and pain threshold (WDT, CDT, HPT, CPS, PHS)
- warm (C-warm-fiber); cold (A-cold-fiber)
- heat pain (C-nociceptors), cold pain (C- or A-nociceptors)
- paradoxical heat sensation during cold (C-nociceptors)
Mechanical detection threshold (MDT, A-low threshold mechanoreceptors, v. Frey hairs)
Mechanical pain threshold (MPT, A-fiber)
Mechanical pain sensitivity/MPS for pinprick (A-mechanonociceptors)
Mechanical pain sensitivity/MPS for light touch (A-low threshold mechanoreceptors)
Wind-up ratio (WUR, trains of single pinprick stimuli)
Vibration detection threshold (VDT) (A-fiber)
Pressure pain threshold (PPT, deep pain, deep (muscle) nociceptors)
TSA
* Protocol of the German Research Network on Neuropathic Pain

16. II) Stiasny-Kolster K, Magerl W, Oertel WH, Treede RD (2008)
Quantitative Sensory Testing (QST)* in RLS
Study I Study II
n (10 f / 1 m) (31 f / 9 m)
de novo iRLS % %
Age (years) ± ± 13
Duration of RLS (years) ± ± 12
IRLS Score (1 – 40 points) ± ± 6
„Leg symptoms“ (1 – 100) ± ± 15
„Urge to move“ (1 – 100) ± ± 15
I) Stiasny-Kolster K, Magerl W, Oertel WH, Moeller JC, Treede RD Brain 127 (2004)
II) Stiasny-Kolster K, Magerl W, Oertel WH, Treede RD (2008)

17. Quantitative Sensory Testing (QST)* (RLS vs. Control, n= 40)
- Warm (C-fiber) and cold (A-fiber) detection threshold
- Heat and cold pain threshold (C- and A-nociceptors)
normal
Paradoxical heat sensation during cold
Mechanical detection threshold (A-LT MR)
Mechanical pain threshold (A-fiber)
Mechanical pain sensitivity for pinprick (A-)
increased in feet
slightly increased
 significant hyperalgesia
 significant hyperalgesia
- Mechanical pain sensitivity for light touch (A-LTMR)
Wind-up ratio (temporal pinprick pain summation)
Vibration detection threshold (A-fiber)
Pressure pain threshold (deep (muscle) nociceptors)
normal
No involvement of the peripheral sensory system (C-, A-, A-fiber and nociceptors)
* Protocol of the German Research Network on Neuropathic Pain

18. Stiasny-Kolster K, Magerl W, Oertel WH, Treede R-D 2008
Quantitative Sensory Testing (QST) (RLS vs. Control, n= 40)
Paradoxical heat sensation (PHS) during cold
PHS  in feet (p<0.001)
Mechanical detection threshold (MDT)
 in hand (p<0.05)
 in feet (p<0.01)
Mechanical pain threshold (MPT)
 in hand (hyperalgesia, p<0.01)
 in feet (hyperalgesia, p<0.001)
Mechanical pain sensitivity (MPS) for pinprick
 in hand (p< )
 in feet (p< )
Stiasny-Kolster K, Magerl W, Oertel WH, Treede R-D 2008

19. Mechanical hyperalgesia is due to spinal sensitization
Decreased central inhibition
central
Spinal hyperexcitability / sensitization
allodynia / mech. hyperalgesia
(glutamate)
Ectopic discharges
Par/dysästhesias
(sodium channel)
peripheral
Peripheral sensitization of nociceptors
(inflammatory substances)

20. Stiasny-Kolster K, Magerl W, Oertel WH, Treede R-D 2008
Quantitative Sensory Testing (QST) (RLS vs. Control, n= 40)
Paradoxical heat sensation (PHS) during cold
PHS  in feet (p<0.001) central disinhibition
Mechanical detection threshold (MDT)
 in hand (p<0.05)
 in feet (p<0.01)
Mechanical pain threshold (MPT) central disinhibition
 in hand (hyperalgesia, p<0.01)
 in feet (hyperalgesia, p<0.001)
Mechanical pain sensitivity (MPS) for pinprick central disinhibition
 in hand (p< )
 in feet (p< )
Stiasny-Kolster K, Magerl W, Oertel WH, Treede R-D 2008

21. Therapy of plus symptoms in neuropathy
Decreased central inhibition
Opioide
Amantadin
Spinal hyperexcitability / sensitization
allodynia / mech. hyperalgesia
(glutamate)
Ectopic discharges
Par/dysästhesias
(sodium channel)
Carbamazepin (sodium channel)
Gabapentin (calcium channel > glutamate release)
Pregabalin (calcium channel > glutamate release)
Peripheral sensitization of nociceptors
(inflammatory substances) 21

22. Descending inhibition systems
Monoamines: Norepinephrin Serotonin (5-HT) Dopamine Peptides: Cholecystokinine (CCK) Neurotensine (NT) Endogenous opioides: Endogenous cannabinoides:
Dopaminergic mechanism and pain control
(Wood PAIN 120 (2006) )
Placebo analgesia
(Levine et al. Lancet 2 (1978) )
Stress induced analgesia
(Hohmann et al. Nature 435 (2005) )

23. Treatment of RLS
Oertel et al. Mov Disord 2007

24. Spinal sensitization in RLS
Cortical
Iron
Subcortical
Dopamin
Hypothalamus (A11), Amygdala, PAG, …
dysfunctional descending control
Iron
PLM
Dopamin
Spinal sensitization
spinal
Mechanical hyperalgesia
ascending afferent input
peripheral

25. - - - Model of decreased pain inbition in RLS Descending inhibition
- 66 % n.s.
Levodopa
Pain -
Touch -
Paradoxical heat sensation
Stiasny-Kolster K, Magerl W, Oertel WH, Treede R-D 2008

26. Cabergoline effects on somatosensory profile (n = 11)
Abnormal mechanical pain sensitivity (MPS) and threshold (MPT)
feet
Stiasny-Kolster K, Magerl W, Oertel WH, Treede R-D in preparation

27. hands Abnormal mechanical pain sensitivity (MPS) and threshold (MPT)
Stiasny-Kolster K, Magerl W, Oertel WH, Treede R-D in preparation

28. Nocizeptive system in RLS
A11
spinal
A11 DA cell group from wich a selective
antinociceptive action could be electrically
evoked and which was mediated by
dopamine at the level of the dorsal horn
Spinal hyperexcitability
Fleetwood et al. J Physiol 1988

29. Anti-nocizeptive effect of dopamine
L-DOPA
Dopamine agonist
A11
Reduction of
spinal hyperexcitability
>>> RLS symptoms 
spinal

30. Increased excitability of the spinal flexor reflex during sleep in RLS
Flexor reflex = spinal escape reflex elicited by pain stimuli at the sole
Threshold 
Spread 
Duration 
>>> Increased spinal excitability and / or
>>> Decreased supraspinal inhibition
Bara-Jimenez et al. 2000

31. Increased excitability of the spinal flexor reflex during sleep in RLS
Flexor reflex = spinal escape reflex elicited by pain stimuli at the sole
= is similar to PLM
spontaneous PLM
restless legs patient
flexor reflex
>>> Increased spinal excitability and / or
>>> Decreased supraspinal inhibition
Bara-Jimenez et al. 2000

32. Spinal sensitization in RLS
Cortical
Iron
Subcortical
Dopamin
Hypothalamus (A11), Amygdala, PAG, …
dysfunctional descending control
Iron
PLM
Dopamin
Spinal sensitization
spinal
Mechanical hyperalgesia
Increased excitability of flexor reflex
ascending afferent input
peripheral

33. 13 untreated RLS patient (3 males, 57.9 ± 13.4 years)
Gait analysis in RLS
13 untreated RLS patient (3 males, 57.9 ± 13.4 years)
8 control subjects (3 males, 53.9 ± 16.5 years)
IRLS score: 26.4 (18 – 35) points
Recordings between 10 and 11 a.m.
Paci, ..., Ferri et al. Sleep Medicine August 2008

34. opto-electronic infrared camera system (6TVC) with two force plates
Gait analysis in RLS
opto-electronic infrared camera system (6TVC) with two force plates
Three video cameras recorded the images of the patient’s walking
Kinematics and EMG data were collected during at least 18 gait cycles
8 surface EMG of tibialis anterior, gastrocnemius lateralis and medialis, soleus muscles of both legs
Paci, ..., Ferri et al. Sleep Medicine August 2008

35. Gait kinematics in RLS (4 steps)
While start of extension of the knee and maximum dorsal flexion of the ankle
Controls: relative silence of the gastrocnemius muscles
RLS: abnormal activation of gastrocnemius muscles
Paci, ..., Ferri et al. Sleep Medicine August 2008

36. Subclinical gait abnormality in RLS
While start of extension of the knee and maximum dorsal flexion of the ankle
there is abnormal activation of gastrocnemius muscles in RLS patients synchronized with the maximum activity of the contralateral muscles
„ possibly due to impaired supraspinal inhibition with possible action on spinal structures involved in gait control „ (A 11 neurons)
Paci, ..., Ferri et al. Sleep Medicine August 2008

37. Spinal sensitization in RLS
Cortical
Iron
Subcortical
Dopamin
Hypothalamus (A11), Amygdala, PAG, …
dysfunctional descending control
Iron
PLM
Dopamin
Spinal sensitization
spinal
Mechanical hyperalgesia
Increased excitability of flexor reflex
Gait abnormalities
ascending afferent input
peripheral

38. Conclusion
Sensory symptoms and pain are a characteristic feature in RLS
The nociceptive system seems to play a crucial rule in the pathophysiology of RLS
Specific nociceptive pattern in RLS
Several studies point towards a spinal hyperexcitability and / or impaired supraspinal inhibition