Baclofen Intratecale e Stato Vegetativo

Marco SaragraveRiabilitazione in Assistenza Intensiva (RAI)

S Raffaele - Cassino

Conseguenze della prima osservazione

bull Su quali basi affermiamo che il recupero osservato egrave correlato allrsquoinfusione intratecale di Baclofen

bull Per quale ragione abbiamo trascurato lrsquoipotesi che il paziente possa essersi ldquosbloccatordquo da un punto di vista motorio

bull Abbiamo sviluppato una o piugrave teorie per spiegarci il fenomeno osservato

bull Abbiamo proseguito con unrsquoosservazione su una casistica piugrave ampia di soggetti

J Neurotrauma 2009 Mar 26 [Epub ahead of print]

Defining consciousness lessons from patients and modern techniquesSaragrave M Pistoia F

Istituto San Raffaele Post-Coma and Rehabilitation Care Unit Cassino Italy marcosarasanraffaeleit

The purpose of this commentary is to expound the possible role of case-reports in exploring consciousness gradations from the vegetative state and minimally conscious state to full consciousness Peer-reviewed literature has never produced so much case-series and single case reports as in this field thus resulting in a wide collection of short-reports related to clinical prognostic and speculative issues Most relevant case reports are reviewed with a view to highlight their merits and limitations in favouring the development of a case-report based knowledge covering various aspects of disorders of consciousness

Conseguenze della prima osservazione

bull Su quali basi affermiamo che il recupero osservato egrave correlato allrsquoinfusione intratecale di Baclofen

bull Per quale ragione abbiamo trascurato lrsquoipotesi che il paziente possa essersi ldquosbloccatordquo da un punto di vista motorio

bull Abbiamo sviluppato una o piugrave teorie per spiegarci il fenomeno osservato

bull Abbiamo proseguito con unrsquoosservazione su una casistica piugrave ampia di soggetti

J Neurotrauma 2009 Mar 26 [Epub ahead of print]

Defining consciousness lessons from patients and modern techniquesSaragrave M Pistoia F

Istituto San Raffaele Post-Coma and Rehabilitation Care Unit Cassino Italy marcosarasanraffaeleit

The purpose of this commentary is to expound the possible role of case-reports in exploring consciousness gradations from the vegetative state and minimally conscious state to full consciousness Peer-reviewed literature has never produced so much case-series and single case reports as in this field thus resulting in a wide collection of short-reports related to clinical prognostic and speculative issues Most relevant case reports are reviewed with a view to highlight their merits and limitations in favouring the development of a case-report based knowledge covering various aspects of disorders of consciousness

J Neurotrauma 2009 Mar 26 [Epub ahead of print]

Defining consciousness lessons from patients and modern techniquesSaragrave M Pistoia F

Istituto San Raffaele Post-Coma and Rehabilitation Care Unit Cassino Italy marcosarasanraffaeleit

The purpose of this commentary is to expound the possible role of case-reports in exploring consciousness gradations from the vegetative state and minimally conscious state to full consciousness Peer-reviewed literature has never produced so much case-series and single case reports as in this field thus resulting in a wide collection of short-reports related to clinical prognostic and speculative issues Most relevant case reports are reviewed with a view to highlight their merits and limitations in favouring the development of a case-report based knowledge covering various aspects of disorders of consciousness

Post Hoc Ergo Propter Hoc

bull Ersquo la fallacia logica piugrave ldquodiffusardquo consiste nello stabilire una relazione causale fra due eventi dal momento che si succedono nel tempo

bull Normalmente questa fallacia puograve essere esclusa quando si disponga di un gruppo sufficientemente ampio di pazienti

bull Nel caso particolare dei pazienti con SV e MCS dobbiamo tenere in considerazione la grande eterogeneitagrave particolarmente riguardo alla distribuzione delle lesioni

bull Piugrave egrave grande il numero di casi maggiore saragrave la probabilitagrave di includere soggetti non sovrapponibili

Lrsquoesempio dello ZOLPIDEM

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Durante le prime quattro settimane lrsquoincremento alla CRS-R riguardava

soprattutto lrsquoarousal come suggerito dallrsquoascesa selettiva del punteggio dela

scala proprio negli item sensibili allrsquoattivazione

Nei mesi successivi abbiamo osservato una maggior responsivitagrave

comportamentale soprattutto nei pazienti n 1 e n 2 (con recupero di normali

contenuti di coscienza) e nel paziente n3 (con transizione verso uno stato di

coscienza minimo e successiva emergenza dallo stesso come

testimoniato dal recupero dellrsquouso funzionale dellrsquooggetto)

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Lrsquoesempio dello ZOLPIDEM

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Durante le prime quattro settimane lrsquoincremento alla CRS-R riguardava

soprattutto lrsquoarousal come suggerito dallrsquoascesa selettiva del punteggio dela

scala proprio negli item sensibili allrsquoattivazione

Nei mesi successivi abbiamo osservato una maggior responsivitagrave

comportamentale soprattutto nei pazienti n 1 e n 2 (con recupero di normali

contenuti di coscienza) e nel paziente n3 (con transizione verso uno stato di

coscienza minimo e successiva emergenza dallo stesso come

testimoniato dal recupero dellrsquouso funzionale dellrsquooggetto)

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Durante le prime quattro settimane lrsquoincremento alla CRS-R riguardava

soprattutto lrsquoarousal come suggerito dallrsquoascesa selettiva del punteggio dela

scala proprio negli item sensibili allrsquoattivazione

Nei mesi successivi abbiamo osservato una maggior responsivitagrave

comportamentale soprattutto nei pazienti n 1 e n 2 (con recupero di normali

contenuti di coscienza) e nel paziente n3 (con transizione verso uno stato di

coscienza minimo e successiva emergenza dallo stesso come

testimoniato dal recupero dellrsquouso funzionale dellrsquooggetto)

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Durante le prime quattro settimane lrsquoincremento alla CRS-R riguardava

soprattutto lrsquoarousal come suggerito dallrsquoascesa selettiva del punteggio dela

scala proprio negli item sensibili allrsquoattivazione

Nei mesi successivi abbiamo osservato una maggior responsivitagrave

comportamentale soprattutto nei pazienti n 1 e n 2 (con recupero di normali

contenuti di coscienza) e nel paziente n3 (con transizione verso uno stato di

coscienza minimo e successiva emergenza dallo stesso come

testimoniato dal recupero dellrsquouso funzionale dellrsquooggetto)

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Saragrave M Pistoia F Mura E Onorati P Govoni S Arch Phys Med Rehabil 2009 In Press

Durante le prime quattro settimane lrsquoincremento alla CRS-R riguardava

soprattutto lrsquoarousal come suggerito dallrsquoascesa selettiva del punteggio dela

scala proprio negli item sensibili allrsquoattivazione

Nei mesi successivi abbiamo osservato una maggior responsivitagrave

comportamentale soprattutto nei pazienti n 1 e n 2 (con recupero di normali

contenuti di coscienza) e nel paziente n3 (con transizione verso uno stato di

coscienza minimo e successiva emergenza dallo stesso come

testimoniato dal recupero dellrsquouso funzionale dellrsquooggetto)

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Durante le prime quattro settimane lrsquoincremento alla CRS-R riguardava

soprattutto lrsquoarousal come suggerito dallrsquoascesa selettiva del punteggio dela

scala proprio negli item sensibili allrsquoattivazione

Nei mesi successivi abbiamo osservato una maggior responsivitagrave

comportamentale soprattutto nei pazienti n 1 e n 2 (con recupero di normali

contenuti di coscienza) e nel paziente n3 (con transizione verso uno stato di

coscienza minimo e successiva emergenza dallo stesso come

testimoniato dal recupero dellrsquouso funzionale dellrsquooggetto)

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Nei mesi successivi abbiamo osservato una maggior responsivitagrave

comportamentale soprattutto nei pazienti n 1 e n 2 (con recupero di normali

contenuti di coscienza) e nel paziente n3 (con transizione verso uno stato di

coscienza minimo e successiva emergenza dallo stesso come

testimoniato dal recupero dellrsquouso funzionale dellrsquooggetto)

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

A modulation confined to spinal cord segmental activities and to neuronal centripetal outputs

reaching the cortex

A modulation of sleep-wake cycles that although present may be dysregulated and interfere with

alertness and awareness

Saragrave et al Arch Phys Med Rehabil 2009 in press

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

In our opinion these filtering systems aimed to prevent an information overload to cortex may be in some degree impaired in patients in VS gating

deficits may cause these subjects to become overloaded by sensory stimuli contributing to a

consciousness impairment also with difficulties in distinguishing the self from nonself This overload may contribute to retard the restoration within the

cortico-thalamo-cortical connections mainly responsible for consciousness recovery

Intrathecal baclofen may modulate the amount of information reaching the cortex by influencing the

GABA related gating systems within the spinal circuits

Saragrave et al Arch Phys Med Rehabil 2009 in press

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

OVERLOAD

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Gate theory

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Pain 1999 AugSuppl 6S121-6

From the gate to the neuromatrix

Melzack R

Department of Psychology McGill University Montreal Quebec Canada

The awareness of the self may be influenced by perceptual stimuli normally modulated by gating

systems acting at thalamic and spinal level as suggested by Melzackrsquos theories on gating and

neuromatrix

Gating

bull La necessitagrave che un segnale venga gestito da sequenze ldquoappropriaterdquo di nodi appartenenti ad una data rete egrave parzialmente garantita dalla capacitagrave di inibizione ldquotrasversalerdquo di ldquonodi parallelirdquo non necessariamente coinvolti in una elaborazione funzionale (in quel dato istante)

bull I sistemi a gating posseggono questa capacitagrave generale sia in modo costitutivo che inducibile

bull Un esempio egrave fornito dallrsquoattenuazione del dolore grazie ad uno stimolo tattile applicato a livello del medesimoello stesso territorio sensitivo

Alternative mechanism

Intrathecal baclofen may favour a modulation of sleep-wake cycles that although present may be

dysregulated and interfere with alertness and awareness

Patients in PVS show preserved wake-sleep cycles However these cycles are commonly irregular as confirmed by the criteria of the

Multi-Society Task Force on PVS and by experimental evidences on atypical sleep

features in these patients

DAleo et al Ital J Neurol Sci 199415347-351 Funct Neurol 19949189-192

Isono et al Brain Inj 200216705-712

Oksenberg et al Sleep 200124703-706

Low baclofen concentrations may reach the brain through cerebrospinal fluid On the bases of the

data sheet of the drug it is possible to estimate that the intrathecal administration of baclofen may give origin to brain levels in the low micromolar range

which may well activate GABAB receptors

Since PVS may be regarded as a disconnection syndrome within cortical-subcortical networks

functionally interlinking wakefulness and awareness the clinical improvement favoured by ITB may at least be partly related to its support to

an enhanced stabilization and coherence of the circadian dynamics

Saragrave et al Arch Phys Med Rehabil 2009 in press

The circuitry whose activity may serve to promote coherent functioning of large populations of cortical and thalamic

neurons with respect to perception attention alertness and awareness is subserved by a proper balance of glutamate activity on NMDA AMPA and metabotropic receptors and

GABA on GABAA and GABAB receptors

Intrathecal baclofen by acting at this level may promote a greater circadian patterns stability

This action may influence the neural plasticity orientate the brain repairing action and favour a clinical improvement

Saragrave et al Arch Phys Med Rehabil 2009 in press

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
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• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31

Low baclofen concentrations may reach the brain through cerebrospinal fluid On the bases of the

data sheet of the drug it is possible to estimate that the intrathecal administration of baclofen may give origin to brain levels in the low micromolar range

which may well activate GABAB receptors

Since PVS may be regarded as a disconnection syndrome within cortical-subcortical networks

functionally interlinking wakefulness and awareness the clinical improvement favoured by ITB may at least be partly related to its support to

an enhanced stabilization and coherence of the circadian dynamics

Saragrave et al Arch Phys Med Rehabil 2009 in press

The circuitry whose activity may serve to promote coherent functioning of large populations of cortical and thalamic

neurons with respect to perception attention alertness and awareness is subserved by a proper balance of glutamate activity on NMDA AMPA and metabotropic receptors and

GABA on GABAA and GABAB receptors

Intrathecal baclofen by acting at this level may promote a greater circadian patterns stability

This action may influence the neural plasticity orientate the brain repairing action and favour a clinical improvement

Saragrave et al Arch Phys Med Rehabil 2009 in press

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
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• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31

The circuitry whose activity may serve to promote coherent functioning of large populations of cortical and thalamic

neurons with respect to perception attention alertness and awareness is subserved by a proper balance of glutamate activity on NMDA AMPA and metabotropic receptors and

GABA on GABAA and GABAB receptors

Intrathecal baclofen by acting at this level may promote a greater circadian patterns stability

This action may influence the neural plasticity orientate the brain repairing action and favour a clinical improvement

Saragrave et al Arch Phys Med Rehabil 2009 in press

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
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