Transcript Diapositiva 1

PERIPHERAL
SPINAL REFLEX
MODEL OF RLS
MODELS
Mauro Manconi
Center of Sleep Medicine,
Scientific Institute of Research San Raffaele, Milan, Italy
PATHOGENETIC HYPOTHESIS
DOPAMINERGIC SYSTEM
SPINAL HYPEREXCITABILITY
SENSITIVE RLS SYMPTOMS / PLM
DOPAMINERGIC HYPOTHESIS
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Efficacy of dopaminergic treatment
Symptomatic form secondary to antidopaminergic drugs (neuroleptics)
Association with Parkinson Disease
Symptomatic form to iron deficiency
(iron is the coenzyme of tyrosin-hidroxilase)
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Evidences of transcranial magnetic
stimulation
Circadian trend of dopamine production
Low dose of pmx (0.25
mg) is effective in RLS
from the first night of
administration.
These results support
a direct involvement of
the dopaminergic
system in RLS
pathogenesis.
Spinal Cord involvement in RLS
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RLS is may be associated with spinal cord injury
 Hartmann M, Pfister R, Pfadenhauer K. Restless legs syndrome
associated with spinal cord lesions. J Neurol Neurosurg Psychiatry
1999;66:688–689.
RLS is often associated with spinal anesthesia
 Lee MS, Lyoo CH, Kim WC, Kang HJ. Periodic bursts of rhythmic
dyskinesia associated with spinal anesthesia. Mov Disord
1997;12:816-817.
RLS is associated with an increasing in spinal reflex excitability
 Bara-Jimenez W, Aksu M, Graham B, Sato S, Hallett M. Periodic
limb movements in sleep: state-dependent excitability of the spinal
flexor reflex. Neurology 2000;54:1609–1616.
Abnormal hyperexcitability along the entire spinal cord, especially its
lumbosacral and cervical segments
• Provini F, Vetrugno R, Meletti S, Plazzi G, Solieri L, Lugaresi E,
Coccagna G, Montagna P. Motor pattern of periodic limb
movements during sleep. Neurology. 2001 Jul 24;57(2):300-4.
Prospective clinical and c/s MRI study in 82 consecutive MS pts
30 subjects (36.5%) had RLS; and they showed a higher EDSS.
No difference in whole brain,
cerebellar and brainstem T2-LLs. MD
and FA histograms derived metrics of
the normal appearing brain tissues;
basal ganglia MD; number of cervical
cord lesions.
Cervical cord average FA was
significantly reduced in MS patients
with RLS.
PYRAMIDAL
SENSITIVE
SYSTEMS
NEUROPHISIOLOGY
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Spinal Reflex
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Latency FR1 and FR2
normal
Amplitude FR1 and FR2
normal
↓ threshold FR1-2
↑ muscles recruitment
Abnormal FR3 response
Spinal Iperexcitability
FR
PLM
Bara-Jimenez, W., et al., Periodic limb movements in sleep: state-dependent
excitability of the spinal flexor reflex. Neurology, 2000. 54(8): p. 1609-16.
Suprachiasmatic nucleus (SCN)
HYPOTHALAMUS
VIP
VP
Circadian
control
A11 dopaminergic neurons
DOPAMINE
D3
Dorsal horn
SPINAL CORD
D3
Intermediolateral nucleus
(IML)
The diencephalic A11 DA neurons
possessed long axons extending over
several segments and possibly
traversing the entire length of the
spinal cord. It is the first time to report
A10 and A11 DA neuron projections into
the spinal cord in mice
Highest densities of D3 binding were observed in
the superfcial layers of the dorsal horn at cervical
and lumbar levels.
DOPAMINE / 5HT2
CPG
LOCOMOTOR
PATTERN
ALMA
RATIONAL FOR AN ANIMAL MODEL
OF RLS/PLM
LESIONAL MODELS
Methods of
previous attempts
PHARMACOLOGICAL MODELS
GENETIC MODELS
The current tendency in achieving an RLS model is generally
represented by simulation of a symptomatic condition of RLS,
or by a direct interference on the dopaminergic system.
• 10 young and 10 old (16-20 months) rats
• I.P. dayly injection of Haloperidol 0.1-0.2 mg/kg
• 5 days observation of:
• EEG + neck EMG
• Hindlimbs movements (HLM) by magnetic inductive device
located subcutaneusly
• PHLM: 4 consecutive movements with inter-movement interval
ranged from 5 to 60 sec. (No duration criteria)
• 8 sham rats + 11 lesioned rats (wistar)
• steretaxical lesion of spinal cord at T9 level
• 7 days of recording of the following parameters:
• EEG, neck EMG, both gastrocnemious muscles EMG
• movements ranged from 3 to 9 sec. were considered in the analysis