Duchenne Muscular Dystrophy: Neuromuscular Management

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Duchenne Muscular DystrophyNeuromuscular
Management
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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

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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

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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

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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

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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

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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

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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
• Egen Klassifikation functional assessment
• Hammersmith motor scales
• Motor function measure

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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

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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

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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

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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.

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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 lt2 yrs)
• Recommended national vaccination schedule should
  be completed prior to beginning steroid treatment
• Varicella (chicken pox) immunity should be
  established

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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

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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

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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

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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

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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.

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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

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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

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Management of steroid medication

• Dose reduction suggested if intolerable/non-manage
  able 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

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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

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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

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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.

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Side effects general cosmetic
Steroid side effect Recommended monitoring Intervention
Weight gain, obesity and Cushingoid features Particular vigilance needed if patient, parents, or siblings are obese Dietary advice to be reinforced before starting steroids warn about increased appetite Implement proactive dietary management for the entire family, not just the patient Consider change from prednisone to deflazacort Select an alternative regimen
Hirsutism Forewarn parents Does not usually occur to an extent that warrants a change in medication
Acne, tinea, warts More noticeable in teenagers Use ancillary treatment measures (topical prescription) and do not rush to change the GC regimen unless the boy is emotionally distressed
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Side effects general cosmetic (2), behavioural
Steroid side effect Recommended monitoring Intervention
Growth retardation Monitor height at least every 6 months as part of general care (stature often small in DMD even without steroids) Consider endocrine evaluation if growth plateaus
Delayed puberty Monitor Tanner stage Identify any family history of delayed sexual maturation Consider endocrine assessment if notably delayed or patient is upset by the delay
Adverse behavioural changes Identify any baseline mood, temperament, ADHD issues, and advise parents that these often transiently worsen in the initial 6 weeks on GC therapy Decide whether baseline issues should be treated before starting GC therapy (e.g. ADHD counselling or prescription) Consider changing timing of GC medication to later in the day Consider behavioural health referral
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Side effects immune/adrenal suppression
Steroid side effect Recommended monitoring Intervention
Immune/adrenal suppression Advise parents of risk of serious infection and need to promptly address minor infection Advise parents to inform all medical personnel that their child is on steroids and carry steroid alert card Ensure that the GC is not stopped abruptly Obtain varicella immunisation before starting GC therapy confirm with protective serum titre Engage in tuberculosis surveillance Obtain infectious diseases consultation if serious infection occurs Substitute prednisone equivalent if deflazacort is temporarily unavailable Implement intravenous stress-dose hydrocortisone or methylprednisolone coverage for surgery or major illness (no accepted treatment strategy anaesthesia or endocrine consultation recommended) Give intravenous coverage if nothing by mouth
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Side effects hypertension, glucose intolerance,
gastric complications (1)
Steroid side effect Recommended monitoring Intervention
Hypertension Monitor blood pressure as percentile for height and sex at each clinic visit If blood pressure gt99, reduce salt intake, weight reduction If ineffective, refer for possible ACE inhibitor or ß blocker medication
Glucose intolerance Urine dipstick for glucose at clinic visits Enquire about polyuria, polydipsia If urine is glucose-positive, then try fasting or post-prandial blood glucose, and if abnormal, then seek an endocrine consultation
Gastritis / Gastroesophagal Reflux Disease (GERD) Enquire about GERD symptoms (heartburn) Advise parents to report symptoms Avoid NSAIDs Prescribe ranitidine or proton-pump inhibitor and antacid if symptomatic
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Side effects gastric complications (2), cataracts
Steroid side effect Recommended monitoring Intervention
Peptic ulcer disease Advise parents of risk and to report symptoms History of gastritis, GERD, abdominal pain, or faecal blood Test stool for blood if anaemic or suggestive history Avoid NSAIDs Prescribe ranitidine or proton-pump inhibitor and antacid if symptomatic Seek gastrointestinal consultation
Cataracts Annual ophthalmological examination Consider switching from deflazacort to prednisone if cataracts evolve that affect vision Seek ophthalmology consultation
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Side effects bone demineralisation
Steroid side effect Recommended monitoring Intervention
Bone demineralisation and increased fracture risk Take careful fracture history Annual DEXA to monitor bone density Annual monitoring of 25-hydroxy vitamin D blood concentration (ideally late winter in seasonal climates) and supplement with vitamin D3 if level is lt32 nmol/L Dietitian should assess calcium and vitamin D intake For 25-hydroxy vitamin D concentration 2031 nmol/L, give 1000 IU orally twice daily, for lt20 nmol/L, give 2000 IU orally twice daily Recheck serum 25-hydroxy vitamin D concentration again after 3 months on therapy Encourage weight-bearing activities Take multivitamin supplements with vitamin D3 Consider bisphosphonates, such as pamidronate
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Side effects myoglobinuria
Steroid side effect Recommended monitoring Intervention
Myoglobinuria Enquire about abnormal coloration of urine after exercise, urine testing Advise avoidance of excessive eccentric (eg, descending stairs, squatting down, trampolining) and resistive exercise Commence renal investigations if persistent
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Schema for initiation of GC medication
Prednisone Deflazacort
0.75mg/kg/day First line unless pre-existing weight and/or behavioural issues favour deflazacort 0.9mg/kg/day Consider as first line when pre-existing weight and/or behavioural issues
Age lt2 years Age 2-5 years Age 6 years
Improving (typical) GC initiation not recommended Plateau (uncommon) monitor closely Decline (atypical) consider alternative diagnoses/concomitant pathology Improving GC initiation not recommended Plateau GC initiation recommended Decline GC initiation highly recommended Improving (uncommon) consider BMD Plateau GC initiation highly recommended Decline GC initiation highly recommended Non-ambulatory refer to text
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Schema for management of GC medication
If any side effects are manageable and tolerable
Incremental increase in dose for growth to maximum weight of 40kg (prednisone 30mg/day or deflazacort 36mg/day) If in functional decline and on subtarget dose, increase to target dose Continue even when non-ambulatory for retarding of scoliosis, decline in pulmonary function tests, and possible heart failure.
If side-effects unmanageable/intolerable change in GC regimen necessary
Reduce daily dosage by 25-33 and reassess in 1 month If side-effects are still unmanageable and intolerable Consider lowering additional 25 on daily schedule minimum effective daily dose of prednisone is approximately 0.3mg/kg/day If weight gain/behaviour are main issues, consider change to deflazacort or high-dose weekend If patient/parents about to abandon treatment entirely, consider 10/10 or 10/20 intermittent dose
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Alternative GC dosing strategies
Prednisone dose Deflazacort dose Comments In case of side-effects
Alternate day 0.75-1.25mg/kg every other day 2mg/kg every other day Less effective but consider when daily schedule has side-effects that are not effectively managed or tolerated Must reduce dose if side-effects are not manageable or tolerable
High-dose weekend 5mg/kg given each Friday and Saturday Not yet tested Less data on effectiveness as compared to a daily schedule, especially if weight gain/behavioural issues are problematic Must reduce dose if side-effects are not manageable or tolerable
Intermittent 0.75mg/kg for 10 days alternating with 10-20 days off medication 0.6mg/kg on days 1-20 and none for the remainder of the month Less effective, but has fewer side effects. Considered the least effective, but possibly best tolerated regimen before abandoning steroid treatment altogether Must reduce dose if side-effects are not manageable or tolerable
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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