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