Atualização das recomendações do consenso brasileiro para distrofia muscular de Duchenne

Araujo, Alexandra Prufer de Queiroz Campos; Saute, Jonas Alex Morales; Fortes, Clarisse Pereira Dias Drumond; França Jr, Marcondes Cavalcante; Pereira, Jaqueline Almeida; Albuquerque, Marco Antonio Veloso de; Carvalho, Alzira Alves de Siqueira; Cavalcanti, Eduardo Boiteux Uchôa; Covaleski, Anna Paula Paranhos Miranda; Fagondes, Simone Chaves; Gurgel-Giannetti, Juliana; Gonçalves, Marcus Vinicius Magno; Martinez, Alberto Rolim Muro; Coimbra Neto, Antônio Rodrigues; Neves, Flavio Reis; Nucci, Anamarli; Nucera, Ana Paula Cassetta dos Santos; Pessoa, Andre Luis Santos; Rebel, Marcos Ferreira; Santos, Flavia Nardes dos; Scola, Rosana Herminia; Sobreira, Cláudia Ferreira da Rosa

doi:10.1055/s-0043-1761466

Brazilian Academy of Neurology • Arq. Neuro-Psiquiatr. 81 (01) • 2023 • https://doi.org/10.1055/s-0043-1761466 linkcopiar

Atualização das recomendações do consenso brasileiro para distrofia muscular de Duchenne

Autoria SCIMAGO INSTITUTIONS RANKINGS

Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.

Palavras-chave
Distrofia Muscular de Duchenne; Consenso; Guia de Prática Clínica; Diagnóstico; Testes Genéticos; Esteroides; Reabilitação; Tratamento Farmacológico; Padrão de Cuidado; Desenvolvimento de Medicamentos

Topic	Question
Diagnosis	Any new genetic tests? Any modification to the previous practice guideline? Methods to increase early diagnosis?
Steroid therapy	New publications comparing regimens and/or drugs? Any modification on starting age? On conducting through different stages of DMD? Alternative drug?
Rehabilitation	New publications on strength exercises, orthoses, or pulmonary care recommendations? Definition of assessments in clinical practice? Definition of DMD stages to implement each recommendation?
Systemic care	New publications on heart assessment and protection? On bone health and orthopedic intervention? New recommendation on vaccines?
New perspectives	Critical review on approved specific drugs after phase 3 clinical trials. Any other new perspective?

Drug (dose- regimen)	Favorable features	Disadvantages	Follow-up schedule*
Deflazacort (0.9 mg/Kg - daily)*	Fewer mineralocorticoid effects; less weight gain	Cataracts; high-priced; unavailable in the Brazilian public health care system	2/year
Prednisone (0.75 mg/Kg - daily)**	Reasonable cost; available in the Brazilian public health care system	Higher risk of bone decalcification; more weight gain	2/year
Prednisone (5 mg/kg on Saturday and Sunday)	Low cost; available in the Brazilian public health care system	Higher risk of bone decalcification; more weight gain	2/year
Prednisolone (0.75 mg/Kg - daily)***	Low cost	Higher bone decalcification risk; more weight gain	2/year
Prednisolone (0.75 mg/Kg - 10 days on and 10 days off) ****	Low cost; fewer side effects	Higher risk of bone decalcification; more weight gain	3/year

Drugs and vaccines
Vitamin D⁵⁸	Prophylaxis in boys with DMD (> 1 year): 1,000 IU/day; Treatment (deficiency if 25-OH-vitamin D levels < 12 ng/ml): 1-12 years: 3,000-6,000 IU/day (12 weeks); > 12 years: 6,000 IU/day (12 weeks). After treatment, keep regular use of prophylactic doses.
Calcium carbonate (1g = 400 mg of elemental calcium)	Supplement if there is vitamin D deficiency 40-80 mg/kg/day of elemental calcium, oral, 8/8h (4 weeks).
Ferrous sulphate⁶⁰	Oral iron (dose of 3 to 6 mg of elemental iron/kg/day), fractionated or in a single dose, for 6 months or until replacement of body stores confirmed by normalization of hemoglobin, MCV, HCM, serum iron, transferrin saturation, and serum ferritin.
Biphosphonates⁵⁵-⁵⁷	Measure cystatin-C or, if unavailable, creatine clearance; Oral use is not recommended; Pamidronate: 6-9mg/kg/year IV every 3-4 months; Zoledronic acid: 0.1 mg/kg/year every 3 to 4 months.
Pneumococcal conjugate vaccine (Pn10 or Pn13)	2, 4, and 12 months.
Pneumococcal polysaccharide vaccine (Pn23)	One dose after the age of 2 years.
Influenza vaccine	Annual dose from 6 months of age.
Yellow fever vaccine	Contraindication if the subject is using prednisone 2 mg/kg/day or equivalent.
Angiotensin-converting enzyme inhibitors	Preferred use of enalapril: 0.1 to 0.5mg/kg/day in 1 to 2 doses; If not, an alternative is captopril: 6 years to adult age: 12.5 mg/dose, 2x/day; adults: 25 mg/dose, 2-3x/day.
Beta-blockers	Preferred use of carvedilol: 0.1 to 0.4 mg/kg/day (maximum of 1 mg/kg/day), 2x/day.
Other drugs used in cardiac management	Espironolactone: 1-3 mg/kg/day; Ivabradine: 2.5 mg 2x/day until 7.5 mg 2x/day;⁵²

	Stage 2	Stage 3	Stage 4	Stage 5
General care		Outline a transition plan with the patient and family
		Attention to fluid intake and constipation
		Consider swallowing assessment⁶¹
				Assess nutritional and swallowing status. Consider gastrostomy
Bone health and orthopedic management		Monitor scoliosis on every medical visit (physical inspection) and on regular imaging. Provide adaptation of the wheelchair. Eventually, in some patients, surgical spinal fusion may be needed²,⁴,⁵⁶ (level of evidence: 5D; class of recommendation: D)
		To screen for osteopenia, thoracolumbar spine radiography (ask for Genant Score Calculation to be calculated by a radiologist) is recommended biannually when using corticosteroids and less frequently in those patients not receiving steroids or at any time in axial pain. If available, a dual-energy x-ray absorptiometry scan can help monitor the bone over time⁴,⁵⁶ (level of evidence: 5D, class of recommendation: D; expert opinion: 38.5% strongly agree; 46.2% agree)
			If bisphosphonates use is required, measure cystatin-C before each infusion (risk of renal failure) (expert opinion: 38.5% strongly agree; 38.5% agree). The use of alendronate or oral bisphosphonates is not recommended (►Table 3)²,⁵⁶ (level of evidence: 5D; class of recommendation: D; expert opinion:.1% agree; 38.5% disagree)
Respiratory management	Annual pulmonary function (spirometry, maximal respiratory pressures, and peak cough flow) (level of evidence 2B, class of recommendation B)
	Implementation of proactive techniques for pulmonary recruitment
	Consider type-1 polysomnography in patients with signs of sleep-disordered breathing, overweight, and those who fail to perform lung function tests well.
		Assessment of the presence of dyspnea in different situations, dysphagia, and signs and symptoms of alveolar hypoventilation*
			With loss of ambulation, perform a pulmonary functional assessment at least twice a year, with spirometry, maximal respiratory pressures and peak cough flow, oximetry, and assessment of CO2, or gasometry.
			Annual polysomnography with CO2 measurement
			Consider ventilatory support
				Ventilation by tracheostomy has been an increasingly controversial topic and should be a decision shared with the patient and their family (level of evidence: 5D; class of recommendation: D)
Cardiac management		Annual Holter monitoring starting at age of 10 years in patients with normal electrocardiogram and starting at any age in the presence of a cardiac arrhythmia
				Consider heart transplantation (patients with good lung function and mild peripheral muscle change)
				Consider implantable cardioverter defibrillators (ICDs) if a symptomatic and complex arrhythmia is present
Mental health	Attention to learning difficulties in school and cognitive and behavioral comorbidities
				Special attention to mental health

Test name	Equipment	Target measure
PEMax	Manometry	Expiratory muscle strength
PIMax	Manometry	Inspiratory muscle strength
Peak flow	Peak flow	Assessment of the mobilization efficacy of cough and bronchial secretion
SNIP	Manometry	Inspiratory muscle strength
VFC	Spirometry	Pulmonary capacity assessment
PEF	Spirometry or peak flow	Indirect pulmonary capacity assessment through forced expiratory flow

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