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 – 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 – Egen Klassifikation 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: general & cosmetic

Steroid side effect

Weight gain, obesity and Cushingoid features Hirsutism

Recommended monitoring

Particular vigilance needed if patient, parents, or siblings are obese Dietary advice to be reinforced before starting steroids; warn about increased appetite Forewarn parents Acne, tinea, warts

Intervention

Implement proactive dietary management for the entire family, not just the patient Consider change from prednisone to deflazacort Select an alternative regimen More noticeable in teenagers Does not usually occur to an extent that warrants a change in medication Use ancillary treatment measures (topical prescription) and do not rush to change the GC regimen unless the boy is emotionally distressed

Side effects: general & cosmetic (2), behavioural

Steroid side effect

Growth retardation Delayed puberty Adverse behavioural changes

Recommended monitoring

Monitor height at least every 6 months as part of general care (stature often small in DMD even without steroids) Monitor Tanner stage Identify any family history of delayed sexual maturation Identify any baseline mood, temperament, ADHD issues, and advise parents that these often transiently worsen in the initial 6 weeks on GC therapy

Intervention

Consider endocrine evaluation if growth plateaus Consider endocrine assessment if notably delayed or patient is upset by the delay 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

Side effects: immune/adrenal suppression

Steroid side effect

Immune/adrenal suppression

Recommended monitoring

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

Intervention

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

Side effects: hypertension, glucose intolerance, gastric complications (1)

Steroid side effect

Hypertension Glucose intolerance Gastritis / Gastroesophagal Reflux Disease (GERD)

Recommended monitoring

Monitor blood pressure as percentile for height and sex at each clinic visit Urine dipstick for glucose at clinic visits Enquire about polyuria, polydipsia Enquire about GERD symptoms (heartburn) Advise parents to report symptoms

Intervention

If blood pressure >99%, reduce salt intake, weight reduction If ineffective, refer for possible ACE inhibitor or β blocker medication If urine is glucose-positive, then try fasting or post prandial blood glucose, and if abnormal, then seek an endocrine consultation Avoid NSAIDs Prescribe ranitidine or proton pump inhibitor and antacid if symptomatic

Side effects: gastric complications (2), cataracts

Steroid side effect

Peptic ulcer disease Cataracts

Recommended monitoring

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 Annual ophthalmological examination

Intervention

Avoid NSAIDs Prescribe ranitidine or proton pump inhibitor and antacid if symptomatic Seek gastrointestinal consultation Consider switching from deflazacort to prednisone if cataracts evolve that affect vision Seek ophthalmology consultation

Side effects: bone demineralisation

Steroid side effect

Bone demineralisation and increased fracture risk

Recommended monitoring

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 <32 nmol/L Dietitian should assess calcium and vitamin D intake

Intervention

For 25-hydroxy vitamin D concentration 20–31 nmol/L, give 1000 IU orally twice daily, for <20 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

Side effects: myoglobinuria

Steroid side effect

Myoglobinuria

Recommended monitoring

Enquire about abnormal coloration of urine after exercise, urine testing

Intervention

Advise avoidance of excessive eccentric (eg, descending stairs, squatting down, trampolining) and resistive exercise Commence renal investigations if persistent

Schema for initiation of GC medication

0.75mg/kg/day Prednisone First line unless pre-existing weight and/or behavioural issues favour deflazacort Age <2 years Improving (typical): GC initiation not recommended Plateau (uncommon): monitor closely Decline (atypical): consider alternative diagnoses/concomitant pathology 0.9mg/kg/day Age 2-5 years Improving: GC initiation not recommended Plateau: GC initiation recommended Decline: GC initiation highly recommended Deflazacort Consider as first line when pre-existing weight and/or behavioural issues Age ≥ 6 years Improving (uncommon): consider BMD Plateau: GC initiation highly recommended Decline: GC initiation highly recommended Non-ambulatory: refer to text

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

Alternative GC dosing strategies

Alternate day High-dose weekend Intermittent Prednisone dose

0.75-1.25mg/kg every other day 5mg/kg given each Friday and Saturday 0.75mg/kg for 10 days alternating with 10-20 days off medication

Deflazacort dose

2mg/kg every other day

Comments

Less effective but consider when daily schedule has side-effects that are not effectively managed or tolerated Not yet tested Less data on effectiveness as compared to a daily schedule, especially if weight gain/behavioural issues are problematic 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

In case of side effects

Must reduce dose if side effects are not manageable or tolerable Must reduce dose if side effects are not manageable or tolerable Must reduce dose if side effects are not manageable or tolerable

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