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The Management of Childhood Neuromuscular Disease in 2008

A/Prof. Andrew J. KornbergRoyal Children’s HospitalMelbourne, Australia

Neuromuscular Disorders

Muscular dystrophies– Dystrophinopathies– Congenital muscular dystrophy– Limb-Girdle muscular dystrophy– Fascioscapulohumeral muscular dystrophy– Emery-Dreifuss muscular dystrophy– Other

Myotonic dystrophyCongenital myopathiesMyasthenia gravisChannelopathiesSpinal muscular atrophiesHereditary motor and sensory neuropathiesMitochondrial disorders

Normal Muscle Biopsy

Dystrophic Muscle Biopsy

Muscular DystrophyImmunostaining

Normal AbsentReduced

Zatz M et al. Neuromuscul Disord 2003;13:532-544.

1423 5

678

910

PyridoxineNicotinic Acid

CoQ10Creatine

GlutamineOxatomide

IL-1 RAEDTA

TaurinePentoxyfilline

Drugs with Potential to Interrupt Theorized DMD Pathophysiologic Cascades

Muscle Disease TherapyFuture Therapies

1

4

2

3

5

6

7

8

9

10

Pyridoxine + 55%Nicotinic Acid + 50%

CoQ10 + 50%Creatine + 50%

Glutamine + 42%Oxatomide + 50%

IL-1 RA + 37%EDTA + 43%

Taurine + 39%Pentoxyfilline + 50%

Mice are given target drugs or sham treatment daily for 3 months and subjected to involuntary treadmill running for 30 minutes twice per week, then tested for whole-body strength

Granchelli JA et al. Pre-clinical screening of drugs using the mdx mouse. Neuromuscul Disord 2000;10:235-239.

A paediatric Quantitative muscle strength testing (QMT) system is employed as a primary endpoint at each CINRG site where clinical trials are conducted.

Bloorview MacMillan Center, OntarioChildren’s Hospital of VirginiaChildren’s Hospital of PittsburghChildren’s National Medical CenterRoyal Children’s Hospital, Melbourne,

AustraliaTexas Scottish Rite HospitalTulane UniversityUniversity of Leuven, BelgiumUniversity of MississippiUniversity of Puerto RicoUniversity of Tel AvivUniversity of Tennessee, MemphisWashington University at St. Louis

CINRG in Clinical TrialsCooperative International Neuromuscular

Research Group

Duchenne Muscular DystrophyManagement

Multifaceted and best using a multidisciplinary approach

Genetic counselling begins at diagnosis

Management issues include:– Physical

– Emotional

– Social

– Educational

– Vocational

One major problem in bridging the physical and educational issues is intelligence capacity


Maintain Ambulation

Prevent or Treat Contractures

Anticipatory Monitoring

Medical Therapy

Maintain AmbulationAs long as the child with DMD is ambulant, he can usually live a reasonably independent existence and cope with most daily activitiesWhen ambulant, there is also less tendency to develop contractures and scoliosisOnce the child loses ambulation he loses much of his independence and is prone to various complications such as contractures and deformities



Maintain Ambulation



Medical Therapy

Prevent or Treat ContracturesMaintain ambulation

Passive stretching

Night time splints

Surgical release of contractures



Maintain Ambulation



Medical Therapy


Anticipatory MonitoringSchool functioningContracturesBone HealthScoliosisRespiratoryCardiac


Anticipatory MonitoringSchool functioningContracturesBone healthScoliosisRespiratoryCardiac

3

810

11

32

20

12

9

3

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3

6

9

12

15

18

21

24

27

30

33

36

<50 50-59 60-69 70-79 80-89 90-99 100-109 110-119 120+

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IQ RANGE

Normal IQ distributionPMD CasesTOTAL -106

MEAN IQ = 86.1

Distribution Of IQ Scores In DMD Cases

Cohen HJ, Molnar GE, Taft LT. The genetic relationship of progressive muscular dystrophy (Duchenne type) and mental retardation. Dev Med.Child Neurol 1968; 10:754-765.

Duchenne Muscular DystrophyBone Health

Duchenne muscular dystrophy associated with:– Reduced bone mineral density– Increased risk of fractures

Steroids may exacerbate the reduced bone mineral densityIssues:

– How to follow bone mineral density?Z-scores do not predict fracture riskZ-scores lower than aged matched controls throughout life

– Vitamin D and calcium supplementation?No data to show that risk is reducedWho should be supplemented?

– Are there other interventions that are useful?Quinlivan R et al. Neuromuscul Disord 2005;15:72-79.Biggar WD et al. Neuromuscul Disord 2005;15:80-85.

Duchenne Muscular DystrophyScoliosis Surgery

Average age at surgery is about 14 years

To undergo surgery– Spinal curve > 25 degrees

– Vital capacity > 30% of predicted

– No active infection

– Cardiovascular system not compromised

Rate of scoliosis surgery varies from centre to centre

Duchenne Muscular DystrophyScoliosis

Predictable stages of decline

Nocturnal hypoventilation and hypoxia is typical– Nocturnal assisted ventilation may be helpful for symptomatic relief

Respiratory failure typically occurs in the late teens or early 20’s with an insidious onset

– Respiratory status ultimately worsens and is typically associated with demise

Steroids seem to preserve respiratory function

Duchenne Muscular DystrophyRespiratory Management

Exons 48-53 deletions possibly associated with a higher incidenceDilated cardiomyopathy > hypertrophic > conduction defectsSymptomatic in 57% by age 18

– insidious onset– Cardiac death in 10% of cases

Steroids may have long term benefit on cardiac function1

Presymptomatic afterload reduction may be of long term benefit

Markham LW et al. Pediatr Cardiol 2005;26:768-771.

Duchenne Muscular DystrophyCardiac Management

Duchenne Muscular DystrophyCardiac Deficit


Maintain Ambulation



Medical Therapy

Muscular DystrophyManagement

Medical Therapy

Nutritional / Chemical therapy

Drug therapy

Gene therapy– Cell replacement: myoblast transfer therapy

– Gene replacement

– Gene repair

– Gene up-regulation

– Nonsense mutation suppression

– Targeted exon skipping

Muscle DiseaseNutritional / Chemical Therapy

SeleniumVitamin EL-tyrosineL-arginineJuvenTM

Coenzyme Q10GlutamineCreatine monohydrate


Selenium1

– Antioxidant– No benefit shown in clinical studies

Vitamin E1,2

– “Panacea” for many disorders– Antioxidant effect and “energy promoter”– Data in open-label pilot study of vitamin E in DMD2

No significant benefit on strength or progression of disease 1Backman E et al. Acta Neurol Scand 1988;78:429-435.

2Fenichel GM et al. Muscle Nerve 1988;11:1164-1168. 3Hankard RG et al. Pediatr Res 1998;43:222-226.


L-arginineSome studies have shown benefit of L-arginine in mdxmouse

– Increased levels of utrophin and improved resistance to contraction-related muscle fiber injury

L-arginine may activate muscle fibre repair mechanisms, as well as stabilizing their membranes and perhaps improving their handling of calciumMechanism may be via nitric oxideNo evidence of benefit in humans

– Could be some detrimental effects as well– Biologically active


L-tyrosine–Improved endurance and strength in a child with

nemaline myopathy1

–Improvement in secretions and bulbar function2

–No major side effects2

–Dosage used is about 250–500 mg/day2

1Kalita D. J Orthomolec Med 1989;4:70-74.2Wallgren-Pettersson C, et al. Neuromuscul Disord 2003;13:501-507.


Juven– Three key ingredients

HMB (beta-hydroxy-beta-methylbutyrate), arginine and glutamine

– May promote muscle protein synthesis and increase muscle mass

– Studies show benefit in patients with cancer and HIV/AIDS in building lean muscle mass

Benefit has led to many families using this compound– Open label with limited objective measures possible benefit– $150/mo– Trial needed

Neurology, January 11, 2005

Prednisolone

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Deflazacort

CorticosteroidsMechanism of Action

The mechanism of action of steroids in Duchenne muscular dystrophy is not known, but there are a number of theories:– positive effect of steroids on myogenesis– anabolic effect on muscle, resulting in increased muscle

mass– stabilization of muscle fibre membranes– attenuation of muscle necrosis (this is controversial)– effect on intracellular calcium concentrations– immunosuppressive effect with reduction of

mononucleated cells, in particular cytotoxic CD8 cells

CorticosteroidsSide Effects

Cushingoid featuresGrowth failure (childhood)Weight gainBone

– Avascular necrosis– Osteoporosis

Myopathy– Myosin-loss– Type II atrophy

DiabetesSkin: Acne; StriaeHypertensionPsychosis and mood disturbancePseudotumor cerebriEye: Cataracts; GlaucomaInfection

Duchenne Muscular DystrophyTreatment with Steroids (1)

Usually offered at time of decline and frequent falls– Steroids would be offered earlier if:

Long term side effects were not an issueEarly therapy is shown to be important in longer term

– Some preliminary data to suggest this is the case

Rapidly improved strength– Measurable in 10 days– Maximum benefit in 3 months

Slows loss of function for up to 3 years– Prolongs ambulation by up to 2 years– Effect on natural history of disease is not known but may confer benefit

into teens


Optimum studied dose of prednisone 0.75 mg/kg/d– At least 16 studies on nearly 1000 affected children have been published in the last three

decades– Daily superior to alternate days in original studies– Major problems are side effects

Early low dose alternate day steroids1

– Beneficial but weight and growth affected– As steroids are effective in prolonging function, but not in recovering lost function, the

authors propose that treatment be started with low-dose prednisone in DMD

Low-dose, intermittent schedule of steroid2,3

– First 10 days of the month or 10 days on, 10 days off– Beneficial with no effects on growth, weight or bone in early patients

1. Merlini L et al. Muscle Nerve 2003;27:222-227.2. Dubowitz V. Neuromuscul Disord 1997;7:261-267.3. Kinali M et al. Neuromuscul Disord 2002;12 (Suppl 1):S169-S174.


Weekly steroids1– 5-10mg/kg/week over 1-2 days– Efficacy might be as good as daily steroids in pilot studies

CINRG trial– Side effects are minimal with growth and weight not affected

1. Connolly AM et al. Neuromuscul Disord 2002;12:917-925.

Duchenne Muscular DystrophyTreatment with Deflazacort

Deflazacort is an oxazolone derivative of prednisolone, which has anti-inflammatory and immunosuppressive effects

– The therapeutic equivalence is approximately 1.2 mg deflazacort to 1 mg prednisone

– Usual deflazacort dosage studied is 0.9 mg/kg/d

Short-term studies in Germany, Italy, and Argentina suggest that deflazacort can delay the loss of muscle function in DMD

– In those studies the ability to walk continued significantly longer in boys treated with deflazacort in comparison to no treatment

Side effects less frequent overall (in comparison to prednisone)

– Weight, growth less affected in short term studies– Asymptomatic cataracts were documented in a higher percentage of boys

What is a clinical trial?• Research study in human volunteers to answer specific

health questions• The fastest and safest way to find treatments that work

in people and ways to improve health • Interventional trials determine whether experimental

treatments or new ways of using known therapies are safe and effective under controlled environments

• Observational trials address health issues in large groups of people or populations in natural settings

Source: www.clinicaltrials.gov

Why participate in a clinical trial?

• Participants in clinical trials can play a more active role in their own health care

• Gain access to new research treatments before they are widely available

• Help others by contributing to medical research


Who can participate in a clinical trial?

• All trials have guidelines about who can participate• Inclusion/exclusion criteria is an important principle of

medical research that helps to produce reliable results • The criteria are used to identify appropriate participants

and keep them safe and help ensure that researchers will be able to answer the questions they plan to study


What happens during a clinical trial?

• The clinical team includes: doctors and nurses as well as other health care professionals

• The team: – Checks the health of the participant at the beginning of the

trial– Gives instructions for participating in the trial– Monitor the participants carefully during the trial– Stay in touch after the trial is completed

• Clinical trial participation is most successful when the protocol is carefully followed


What are the different types of clinical trials?

• Treatment trials: test experimental treatments, new combinations of drugs, or new approaches to treatments

• Prevention trials: look for better ways to prevent disease

• Diagnostic trials: find better tests or procedures for diagnosing particular disease

• Screening trials: detect certain disease or conditions• Quality of Life trials: explore ways to improve comfort

and quality of life


Clinical Trials - History• 1747 – Lind: Experiment with untreated control group (disease:

scurvy)• 1800 – Waterhouse: US based smallpox trial• 1863 – Gull: First use of placebo treatment• 1858 – Duchenne de Boulogne: First described the disease and

tested different treatments • 1931 – Amberson: First randomized trial• 1937 – NIH started grant support • 1944 – Introduction of multicenter studies• 1980s – Clinical Investigators in Duchenne Dystrophy (CIDD group)

was formed and started first trials with Duchenne

CINRG Clinical Trials

• CINRG was formed in 1999 • Academic multi-center network to facilitate clinical

trials for DMD• Central site is located at Children’s National

Medical Center in Washington, DC• Largest clinical trial network for DMD with 22

centers worldwide

Quantitative Muscle Testing

• Quantitative muscle testing (QMT) is a sensitive and precise method to test muscle strength

• CINRG developed a pediatric version, which includes video game-like features

Muscle Testing output

Breathing Testing output

Duchenne Muscular DystrophyTreatment Strategies

Type of Mutations

Gene replacement

Cell transferExon skipping

Nonsense mutation read-

through

Improve dystrophic

muscle health

Gene deletions X X X

Gene duplications X X X

Nonsense mutations X X X X

Other mutations X X

Stage of Development

Pre-clinicalEarly clinical trial



ClinicalClinical trial

PTC124• A small molecule that reads through a premature stop signal

in the gene that would prevent production of full-length dystrophin protein

• PTC Therapeutics granted orphan drug status from the FDA to investigate the potential of PTC124 in the treatment of cystic fibrosis and DMD

• Phase 2 human clinical trial in DMD: preliminary human trial data released Oct 2006

STOP

Neuromuscular Disease TherapySummary

These are exciting times as there is a greater understanding of the genetic, molecular, and physiological genesis of the neuromuscular disorders

– The better understanding will hopefully lead to new and hopefully effective therapies

Rapid pre-clinical screening in animal models of drugs and genetic treatments will lead to more efficient studies of their effectiveness in humansImprovement in the way we assess response to therapy in human studies, and the development of cooperative groups such as CINRG will allow the rapid study of new therapies

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