“Dalle Linee Guida alla Best Practice in fisioterapia.” › files › 2018 › 05 ›...
Transcript of “Dalle Linee Guida alla Best Practice in fisioterapia.” › files › 2018 › 05 ›...
XII Congresso Scientifico Regionale AIFI Liguria
“Dalle Linee Guida alla Best Practice in fisioterapia.”
Rapallo, 19 maggio 2018
Le linee guida in ambito neurologico: focus sulla
neuropatia di Charcot-Marie-Tooth (CMT)Angelo Schenone
Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno Infantili
Università di Genova
Dalle Linee Guida alla Best Practice
in fisioterapia
Rapallo, 19 maggio 2018Rapporti anche di finanziamento con soggetti portatori d
i interessi commerciali in campo sanitario:
•…Kedrion•…Sigma Tau•…Behring Grifols
Neuromuscular diseases• ARTHROGRYPOSIS
• AUTOSOMAL RECESSIVE SPASTIC ATAXIA OF CHARLEVOIX-SAGUENAY
• PERIPHERAL NEUROPATHIES (GUILLAIN-BARRÉ SYNDROME, CIDP, DIABETES)
• HEREDITARY MOTOR AND SENSORY NEUROPATHY (CHARCOT-MARIE-TOOTH DISEASE)
• MUSCULAR DYSTROPHIES
➢ DUCHENNE MUSCULAR DYSTROPHY
➢ FACIOSCAPULOHUMERAL DYSTROPHY
➢ LIMB-GIRDLE MUSCULAR DYSTROPHY
➢ MYOTONIA CONGENITA
➢ MYOTONIC DYSTROPHY
➢ BECKER MUSCULAR DYSTROPHY
➢ OCULOPHARYNGEAL MUSCULAR DYSTROPHY
• MITOCHONDRIAL MYOPATHY
• MCARDLE’S DISEASE
• MULTICORE MYOPATHY
• MYASTHENIA GRAVIS
• MYOSITIS DISORDERS
• NEMALINE MYOPATHY
• POMPE DISEASE
• SPINAL MUSCULAR ATROPHY
• FRIEDREICH’S ATAXIA
• AMYOTROPHIC LATERAL SCLEROSIS
Classification of Hereditary Neuropathies (Reilly M, Pract Neurol, 2007)
1. Neuropathies in which the neuropathy is the sole or primary part of the disease
• Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth (CMT) disease
• Hereditary sensory (and autonomic) neuropathies
• Hereditary motor neuropathies (distal)
• Hereditary neuralgic amyotrophy
• Familial amyloid polyneuropathy
2. Neuropathies in which the neuropathy is part of a more widespread neurological or multisystem disorder
• Lipid metabolism (leukodistr., lipoprot. deficiency, phyatnic acid storage disease, etc.).
• Porphyrias (acute intermittent, hereditary coproporphyria, etc.).
• Disorders with defective DNA (ataxia teleangectasia, xeroderma pigm, Cockayne sindr.).
• Neuropathies associated with mitochondrial diseases (MNGIE, NARP, SANDO, POLG)
• Neuropathies associated with hereditary ataxias (SCA, Friedreich’s ataxia, etc)
• Inherited Spastic Paraparesis (BSCL2, REEP1, Atlastin, KIF1A)
Charcot-Marie-Tooth (CMT) Neuropathy
1:2500 individuals affected
Primary demyelinating (AD: CMT1; AR: CMT4)
✓ Severely reduced motor nerve conduction velocities
(<38 m/sec.)
✓ Neuropathological evidence of demyelination and
onion bulbs formation
Primary axonal (AD:CMT2; AR:
CMT2AR)
✓ Normal or mildly reduced motor
nerve conduction velocities (>38
m/sec.), reduced amplitude of
compound muscle action
potentials
✓ Neuropathological evidence of
axonal loss (mild)
CMT1 X-linked (CMT1X)
✓ Combine features of the axonal and demyelinatingtypes
Dominant Intermediate
✓ Autosomal dominant with intermediate conductionvelocities (DI-CMT)
Timmerman et al, Genes, 2014> 80 genes
Possible therapeutic approaches to CMT and related disorders
Molecular genetic/gene therapies
Stem cells therapies
Pharmacologic therapies
Rehabilitation therapy
Specific
«Cross sectional»
Specific
«Cross sectional»
«Cross sectional»
«Cross sectional»
From: Advancements of medical biotechnology in gene therapy. B. Victor
Shy M, PNAS, 2016, vol. 113 (17), 4552-4554
Gene therapy approaches in mouse models of CMT
CMTX
Intrathecal gene therapy rescues a model of demyelinating peripheralneuropathy A. Kagiavaa, et al. Proc Natl Acad Sci, 113: E2421-E2429. 2016
• Gene delivery approach via a single lumbar intrathecal
injection
• Stable Schwann cell gene expression in an unexpectedly
widespread distribution—the lumbar spinal roots and along
the entire length of the femoral and sciatic nerves
• Treat a mouse model of CMT1X resulted in significant
behavioral, functional, and morphological improvement,
providing an important advance toward treating inherited
neuropathies.
Behavioral and physiological improvement in intrathecally
treated Cx32 KO mice.
Intrathecal gene therapy rescues a model of demyelinating peripheralneuropathy A. Kagiavaa, et al. Proc Natl Acad Sci, 113: E2421-E2429. 2016
Improvement of anterior lumbar spinal root demyelination
and inflammation in 8-mo-old Cx32 KO mice following
intrathecal gene therapy with the LV.Mpz-GJB1 vector
Intrathecal gene therapy rescues a model of demyelinating peripheralneuropathy A. Kagiavaa, et al. Proc Natl Acad Sci, 113: E2421-E2429. 2016
Improvement of demyelination and inflammation in femoral motor nerve branches and midsciatic nerves of 8-mo-old Cx32 KO mice
following intrathecal gene therapy.
Intrathecal gene therapy rescues a model of demyelinating peripheralneuropathy A. Kagiavaa, et al. Proc Natl Acad Sci, 113: E2421-E2429. 2016
This study demonstrates that a single intrathecal lentiviral
gene delivery can lead to Schwann cell-specific expression in
spinal roots extending to multiple peripheral nerves. This
clinically relevant approach improves the phenotype of an
inherited neuropathy mouse model and provides proof of
principle for treating inherited demyelinating neuropathies.
Possible therapeutic approaches to CMT and related disorders
Molecular genetic/gene therapies
Stem cells therapies
Pharmacologic therapies
Rehabilitation therapy
Specific
«Cross sectional»
Specific
«Cross sectional»
«Cross sectional»
«Cross sectional»
High-quality evidence indicates that ascorbic acid does not improve the
course of CMT1A in adults in terms of the outcome parameters
used. According to low-quality evidence, ascorbic acid does not improve
the course of CMT1A in children. However, CMT1A is slowly
progressive and the outcome parameters show only small change over
time. Longer study durations should be considered, and outcome
parameters more sensitive to change over time should be designed and
validated for future studies.
MRI outcome measures can monitor intramuscular fat
accumulation with high responsiveness, show validity by
correlation with conventional functional measures, and detect
muscle water changes preceding marked intramuscular fat
accumulation. Confirmation of our results in further cohorts
with these and other muscle-wasting disorders would suggest
that MRI biomarkers might prove valuable in experimental
trials.
Possible therapeutic approaches to CMT and related disorders
Molecular genetic/gene therapies
Stem cells therapies
Pharmacologic therapies
Rehabilitation therapy
Specific
«Cross sectional»
Specific
«Cross sectional»
«Cross sectional»
«Cross sectional»
Efficacy
Length of treatment
Frequency of treatment
Which treatment
«Cross sectional» rehabilitative approach: physical therapy
• Eight volunteers were fitted with custom AFOs.
• 10 weeks accommodation period: plantar- and dorsiflexor strength was
measured bilaterally.
• Volunteers then walked unbraced and braced, at their preferred pace over
a force platform and instrumented walkway while being tracked with a 12-
camera motion capture system. Strength, spatio- temporal and lower
extremity joint kinetic parameters were evaluated between conditions
(single subject) using the model statistic procedure.
• All participants walked faster (89.4 13.3 vs 115.6 18.0 cm/s) in the braced
condition with ankle strength negatively correlated to speed increase.
• As Δ velocity increased, maximum joint moments during loading response
shifted from the hip joint to the ankle and knee joints.
Conclusion
Subject-specific effects of a custom AFO on gait for CMT patients were
documented. The force-deflection properties of carbon-fiber composite
braces may be important considerations in their design.
Dufek et al, Gait & Postrure 2014
Challenges to Rehabilitation Trials
• Blinding
• Randomization (resistence of patients)
• Ethicity of control groups
• Complexity of interventions (causal contribution of
interventions’ various components)
• Insufficiency of eligible participants (multisite trials)
• Length of F.U.
• Funding
• TreSPE:• 3 months of treatment consisting in 2
session a week, 2 hours each, of Treadmilltraining and SPE
• SPE:• 3 months of treatment consisting in 2
session a week, 2 hours each, ofrespiratory, proprioceptive and stretchingexercise
T0 T1 T2treatment
6 monthsbaseline 3 months
BBS: Berg Balance Scale; SPPB: Short Physical Performance Battery
• Only 6/53 subjects did not complete the protocol
• T1: 89.4% pts improved in at least one OM (no differences between
the two treatment groups)
RESULTS: Primary OMs
Linear mixed model with random intercept and corrected for centre was used to statistically test the longitudinal change at T1 and T2 of all clinical scales. To assess the differences on longitudinal performances the interaction term treatment*time was considered into the model. A p<0.05 was considered statistically significant. Stata (v.14; StataCorp.) was used for the computation.
*
*
*
* p<0.02
Manuscript in preparation
* *
*
RESULTS: Secondary OMs
* p<0.02
QoLFor all subscales of SF36, no consistent differences were noticed in the scores over time comparing the two treatments not even comparing the Physical Composite Score (PCS) or the Mental Composite Score (MCS).
BBS: Berg Balance Scale; SPPB: Short Physical Performance Battery
• Tolerability: SPE and TreSPE treatments are well tolerated and not burdened byoverwork weakness (no deterioration in motor performances nor in the QoL)
• Efficacy: Walking ability (6-MWT and 10-MWT) improves in both groups, withsignificant results for the SPE treatment and no additional effect of aerobicexercise at the treadmill. Improvement in both groups is maintained after 6months
• Efficacy: Balance (BBS and SPPB) improved in both groups at 3 months, with asignificant additional effect of the aerobic exercise at the treadmill especially at 6month. Lower risk of falls?
• Length/frequency of treatment: 3 months/3 times/week, twice/year, with aslight preference for TreSPE, as it allows longer improvement.
Summary results and conclusions
Manuscript in preparation
Francisco Josè de Goya y Lucientes, painter, 1803
Charcot-Marie-Tooth(CMT) Neuropathy
Atrofia peroneale
Pes cavus
Dita a martello
Deformità della mano
Sensor Engineered Glove Test
Software di registrazione e analisi dei dati
Guanto ingegnerizzato
Scheda di acquisizione
Thumb Opposition Test
Tripod pinch strength and thumb opposition are the major determinants of manual dexterity in Charcot-Marie-Tooth disease type 1A.Videler et al. (2010)
• Misura da 0 a 10 la capacità di opposizione
• Nei pazienti CMT è ritenuto uno dei migliori test per la destrezza
• Fornisce un’idea diretta di quanto il paziente riesce ad opporre il pollice alle altre dita
Dinamometria (tripod pinch & hand grip)
Tripod pinch strength and thumb opposition are the major determinants of manual dexterity in Charcot-Marie-Tooth disease type 1A.Videler et al. (2010)
• È un test riproducibile e preciso
• Data la variabilità enorme dei pazienti (e dei controlli sani) è una misura che assume un significato quando si considera la sua variazione nel tempo
Risultati: Sensor Engineered Glove Test
• Discrimina tra controlli sani, pazienti CMT con mano non compromessa (group 1) e pazienti CMT con mano affetta (group 2).
• Il compito alla Massima Velocità (MV) è quello che maggiormente esalta la diversità di performance tra controlli sani e pazienti CMT.
In conclusion, this study supports the existence of the overwork
weakness in CMT. We can speculate that the dexterity and
overall ability of the hands appear more impaired in the DH as a
result of a weakness and incapacity of opposition. Our results
support the importance of avoiding supramaximal exercises and
educating patients to prevent incorrect movements.
RisultatiThumb Opposition Test
(p= 0,94)
(p= 0,01)
Nei pazienti CMT la mano non dominante ha un valore di TOT migliore rispetto alla mano
dominante
Prada et al, JPNS 2018
RisultatiForza
(p< 0,0001) (p= 0,83)
Nei controlli sani è rispettata la «regola del 10%», mentre nei pazienti non esiste una dominanza manuale nella forza
(p= 0,0003) (p= 0,16)
Prada et al, JPNS 2018
RisultatiSEGT
(p< 0,0001) (p= 0,64)
(p= 0,0178) (p= 0,33)
Nei pazienti CMT il valore medio della frequenza tra mano dominante e non dominante non mostra differenza significativa
Prada et al, JPNS 2018
L’importanza della dimostrazione dell’overwork weakness si traduce nella corretta creazione di protocolli riabilitativi che non devono mai provocare uno sforzo massimale
I pazienti dovrebbero essere educati precocemente al corretto utilizzo della mano nelle attività della vita quotidiana
Conclusioni
È possibile rallentare la progressione della malattia dell’arto superiore?
L’overwork weakness è confermata nei pazienti affetti da CMT
Prada et al, JPNS 2018
From: Advancements of medical biotechnology in gene therapy. B. Victor
“Results: In the prespecified interim analysis, there was a least-squares
mean increase from baseline to month 15 in the HFMSE score in the
nusinersen group (by 4.0 points) and a least-squares mean decrease in the
control group (by -1.9 points), with a significant between-group difference
favoring nusinersen (least-squares mean difference in change, 5.9 points;
95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early
termination of the trial.”
GRAZIE PER L’ATTENZIONE