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Duchenne Muscular Dystrophy: Neuromuscular Management. Introduction. Muscles weaken due to lack of dystrophin Regular checkups with specialists are required Steroids are the only drugs which alter the natural history of DMD Should only be prescribed by doctors with appropriate expertise
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Introduction • Muscles weaken due to lack of dystrophin • Regular checkups with specialists are required • Steroids are the only drugs which alter the natural history of DMD • Should only be prescribed by doctors with appropriate expertise • Proactive side-effect management is crucial • No current evidence that other supplements work
Regular Checkups • Neuromuscular specialist every 6 months • Monitor disease progression • Make decisions about new treatments at appropriate times • Anticipate and prevent any problems including side effect prevention and management • Specialist physiotherapist and/or occupational therapist every 4 months
What to measure? • Specific tests vary between clinics • Consistency, experience and regular review important • Areas of assessment include • Strength (force generated at joints) • Range of joint motion (monitor contractures) • Timed tests (e.g. 6MWT, rise from floor, steps) • Motor function scales (e.g. North Star) – different scales may be needed at different times • Activities of daily living (assess whether additional help required to assist independence) • Further information in TREAT-NMD Registry of Outcome Measures www.treat-nmd.eu/rom
Assessments: Strength Testing • Method • Manual muscle testing (MRC scale) • Quantitative myometry (if MRC scale 3-5) • Aims • Serial assessment to identify outliers from expected clinical course • Monitor disease progression, predict functional losses • Assess response to treatment • Monitor muscle imbalance • Ambulatory • Test lower extremity strength by manual muscle testing every 6 months • Non-Ambulatory • Early stages: test upper and lower extremity strength every 6 months • Later stages: value of testing is less certain
Assessments: Range of motion • Method • Goniometry • Aims • Baseline: identify emerging muscle hypoextensibility and joint contractures that might contribute/lead to functional deterioration or musculoskeletal or integumentary problems • To identify need for additional/altered therapeutic/surgical intervetion (i.e. orthoses, splinting, use of standers, iliotibial band lengthening) • Ambulatory • Lower extremities: hip, knee, ankle joints, iliotibial band, hamstrings, gastrocnemius • Non-Ambulatory • Lower extremities: hip, knee, ankle joints, iliotibial band, hamstrings, gastrocnemius • Upper extremities: elbow, wrist, long finger flexors
Assessments: Timed Testing • Method • Standardised use of timed function tests • Aims • Easy and relevant measure of daily functional status and responsiveness to change • Ambulatory • Timed 10m walk • Timed Gowers’ manouvre • Time to climb 4 stairs • Time to rise from chair • Time to put on a shirt may be relevant in late ambulatory stage • Non-Ambulatory • Time to put on a shirt may be relevant in early non-ambulatory stage • Timed testing not applicable in late non-ambulatory stage
Assessments: Motor function scales • Method • Assessment of motor function in specific domains to give a composite score • Aims • Allows monitoring of progression and response to therapy • Ambulatory • Vignos lower extremity scale • North Star Ambulatory Assessment • Motor function measure • Non-Ambulatory • Brooke upper extremity scale • EgenKlassifikation functional assessment • Hammersmith motor scales • Motor function measure
Assessments: Activities of daily living • Method • Assessment of impairment in daily activities in the home, school and community settings • Aims • Highly relevant to targeted input with aids, adaptation, and access to environmental controls • Ambulatory • Frequency of falls, step activity monitoring • Self-care skills • Writing, computer use • Functioning in school and community settings • Non-Ambulatory • Self-care skills • Writing, computer use • Control of manual and electric wheelchair • Functioning in school and community settings
Drug Treatments • Steroids are only evidence-based drug treatment for musculoskeletal DMD symptoms • Effective and safe use is based on regular assessment of function and side-effects • As new evidence is available, these guidelines will be revised
Steroid Treatment: Introduction • Significant experience in steroid use for many conditions • Benefits should be balanced with proactive management of possible side-effects • Use of steroids very important: should be discussed with all families early
Steroids: The Basics • Steroids are the only drugs known to slow decline in muscle strength and motor function in DMD • Goals • Help child walk independently for longer • Minimise later breathing, heart and orthopaedic problems • Can also reduce risk of scoliosis • Prevention/management of side-effects should be proactive and anticipatory. • Early intervention to prevent problems.
Steroids: Starting treatment • Optimal time for starting treatment is when motor skills have reached a plateau (4-6yrs) • Not recommended to start steroids in children who are still gaining motor skills (esp <2 yrs) • Recommended national vaccination schedule should be completed prior to beginning steroid treatment • Varicella (chicken pox) immunity should be established
Steroids: Starting treatment (2) • Decision to initiate treatment should be based on a serial assessment and parental report: care is required if initiating steroid treatment at an initial visit, or as a second-opinion consultation • Starting treatment in non-ambulant boys is an individual decision, which should take into consideration individual risk factors • Many experts recommend continuation of steroid treatment after the loss of ambulation, to preserve upper limb strength, slow scoliosis, and delay decline in respiratory and cardiac function
Steroid Regimes 1 • Two steroids recommended for DMD • Prednisone (also known as prednisolone) • Deflazacort • Believed to work similarly: neither known to be better • Planned trials will provide more knowledge • Choice of steroid depends on • Availability • Cost to family • The way the drug is taken • Perceived side effects
Steroids: Prednisone • Inexpensive, both tablet/liquid fomulations • Recommended starting dose: 0.75mg/kg/day • In ambulatory individuals dosage commonly increased as child grows, to ~40kg in weight • Max dose capped at ~30mg/kg/day • Non-ambulatory teenagers above 40kg: • Dosage often allowed to drift down to 0.3-0.6mg/kg/day range: below cap, but still shows substantial benefits
Steroids: Deflazacort • May have slightly lower risk of weight gain • More expensive than prednisone, available in fewer tablet sizes, and liquid formulation not widely available. • Recommended starting dose: 0.9mg/kg/day • In ambulatory individuals dosage commonly increased as child grows, to ~40kg in weight • Max dose capped at ~36mg/kg/day • Non-ambulatory teenagers above 40kg: • Dosage often allowed to drift down to 0.5-0.7mg/kg/day range: below cap, but still shows substantial benefits
Steroid Regimes 2 • Daily dose of steroids better understood than alternate regimes (trial data may modify this) • Maintenance steroid dose • Balance between growth, individual response, and burden of side-effects • Should be reviewed at every clinic visit, based on test results and tolerability/manageability of side effects • For boys on relatively low dosage (less than starting dose per kg of body weight) who begin to show functional decline, it may be necessary to consider a “functional rescue” adjustment. • The dosage is increased to target, and the individual re-evaluated for any benefit in 2-3 months.
Initiation of steroids in non-ambulatory individuals • No consensus on optimal steroid dosage if initiated in a non-ambulatory individual • Not known how effective this treatment is in preventing scoliosis or stabilising cardiac/respiratory function • This area warrants further study
Steroid management and side effects • Some patients may experience short-lived side-effects (hyperactivity, mood swings) for a few hours after medication is given. Administration in the afternoon may alleviate these difficulties • Before starting/stopping medication, the doctor should be consulted • Doctors should always be informed that a patient is on steroids – especially if considering surgery, or during infection/injury, as steroids can suppress the immune system. • Patients should never stop taking steroids suddenly
Management of steroid medication • Dose reduction suggested if intolerable/non-manageable side-effects occur, with reassessment by phone/clinical visit one month later to assess control of side effects • If daily dosing schedule leads to unmanageable and/or intolerable side effects that do not improve when the dose is reduced, it is appropriate to change to an alternative regime
Management of steroid medication (2) • Steroid therapy should not be abandoned until at least one dosage reduction and change to an alternative regime have been pursued, for both ambulatory and non-ambulatory patients • Should adjustments prove ineffective in making any significant side-effects sufficiently manageable/tolerable, it is necessary to discontinue steroid therapy. • Decision should be made in partnership with the patient and family • Steroids should never be stopped suddenly
Other drugs and supplements • Oxandrolone, an anabolic steroid, is not recommended • Safety in the use of botulinum toxin A (Botox) has not been studied in treatment/prevention of contractures for DMD and is not recommended • No support for systemic use of creatine; if a patient is taking creatine and has evidence of kidney problems it is necessary to discontinue this supplement • Due to a paucity of evidence in published literature, no recommendations can be made about other drugs/supplements, including: • Co-enzyme Q10 • Carnitine • Amino acids (glutamine, arginine) • Anti-inflammatories/antioxidants (fish oil, vitamin E, green tea extract, pentoxifylline) • Herbal/botanical extracts • Additional research is needed in this area
Steroid side effects: recommended monitoring and intervention • Different people will have very different responses to steroids. Some of the more common side-effects are listed below. • Key to successful management is an awareness of potential side-effects, preventing/reducing them where possible.
Side effects: hypertension, glucose intolerance, gastric complications (1)
References & Resources • The Diagnosis and Management of Duchenne Muscular Dystrophy, Bushby K et al, Lancet Neurology 2010 9 (1) 77-93 & Lancet Neurology 2010 9 (2) 177-189 • Particularly references, p186-188 • The Diagnosis and Management of Duchenne Muscular Dystrophy: A Guide for Families • TREAT-NMD website: www.treat-nmd.eu • CARE-NMD website: www.care-nmd.eu
