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Neuromuscular weakness 

Neuromuscular weakness
Chapter:
Neuromuscular weakness
Author(s):

Jeremy Hull

, Julian Forton

, and Anne Thomson

DOI:
10.1093/med/9780199687060.003.0048
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Introduction

Respiratory complications are a major cause of morbidity and mortality in children with neuromuscular diseases. As a group, neuromuscular conditions have a prevalence of around 1 in 3000 children, but respiratory involvement is highly variable between conditions. Weakness of the muscles of respiration results in shallow breathing and an ineffective cough, making these children vulnerable to hypoventilation, atelectasis, pneumonia, and tracheal obstruction from retained respiratory tract secretions. In addition, some children will have poor upper airway tone or airway protection, leading to upper airway obstruction and/or aspiration lung disease. Finally, muscle weakness leads to progressive scoliosis, worsening mechanical failure. Children with respiratory complications fall into two broad groups:

  • infants/young children with severe weakness, some of whom may improve over time;

  • older children who have progressive disease, e.g. boys with Duchenne muscular dystrophy (DMD), or those with progressive scoliosis.

In both groups of children, common problems are:

  • rapid onset of respiratory failure, usually in association with a chest infection;

  • gradual onset of respiratory failure, usually starting during sleep;

  • difficulties in weaning from ventilation after scoliosis or other major surgery.

All these situations are much easier to manage if respiratory assessment and intervention occur before an acute deterioration. Effective management of respiratory problems has a major impact on the quality of life and life expectancy for these children. Thus, assessment of the respiratory status should be part of every medical consultation.

Management of respiratory problems

Assessment

Who should be assessed?

It is hard to predict which children with neuromuscular weakness will have an impaired respiratory function, and therefore assessment of the respiratory health should form part of each medical consultation.

History

Specific information that is helpful in making a respiratory assessment includes the following.

  • General well-being, growth, and assessment of the extent, pattern, and progression of muscular weakness: are they getting stronger or weaker? If ambulant, how far can they walk and how fatigued are they?

  • Nature and strength of cough and the ability to clear respiratory secretions.

  • The ability to feed and swallow: any choking?

  • Any evidence of night-time hypoventilation, e.g.

    • disturbed sleep;

    • difficulty waking in the morning;

    • morning headache;

    • morning nausea (do they usually eat breakfast?);

    • daytime sleepiness, fatigue;

    • difficulty concentrating during the day, including poor school performance.

  • The number and nature of chest infections in the past: are they increasing? Was hospital care required? Was oxygen needed?

  • If there is established scoliosis, is this progressing and is any surgery planned?

Examination

  • Assessment of the child’s strength: proximal, distal, facial, bulbar.

  • Observation of respiratory movements:

    • chest expansion;

    • abdominal movement (is the movement of the diaphragm paradoxical?).

  • Spine: is it straight? Assess with standing and bending forwards, if scoliosis is not obvious.

  • Nutritional status.

  • If the child is able to cooperate, ask them to cough to assess its effectiveness.

  • In an infant particularly, look for evidence of hypoventilation:

    • tachycardia;

    • desaturation;

    • sweating and pallor.

Investigations

  • All children with weakness who are able to carry out the necessary manoeuvres should perform simple spirometry. Weak children may have trouble making a seal with their lips around a standard mouthpiece, and special mouthpieces with a flange inside the lips may help. A slow VC provides the most useful information and is a predictor of susceptibility to infection, the need for respiratory support, and survival in DMD.

  • The ulnar length or arm span can be used, instead of the height, to predict expected lung function values.

  • Cough peak flow is a measurement of cough effectiveness and can be measured using a face mask or mouthpiece connected to a peak flow meter. In adults, a cough peak flow of >160 L/min is needed for an effective secretion clearance, and those with a cough peak flow of <270 L/min are vulnerable to respiratory failure with a minor respiratory infection. These values can be applied for children over the age of 12 years.

  • Respiratory PSG, including CO2 measurements, is often needed to assess the evidence of night-time hypoventilation. Some children with neuromuscular weakness also have abnormal respiratory control (e.g. those with myotonic dystrophy and mitochondrial disease), and this may also be demonstrated by PSG. A common pattern of abnormality is the evidence of hypoventilation seen particularly during active (REM) sleep. Indications for overnight sleep monitoring are:

    • infants with weakness;

    • children with a VC <60% predicted;

    • children with a history suggestive of night-time hypoventilation or OSA;

    • children with recurrent respiratory exacerbations;

    • children with diaphragmatic weakness;

    • children with rigid spine syndromes.

  • Evaluation of swallowing (by videofluoroscopy) and GOR may be required. Aspiration events are common and may precipitate respiratory failure.

Respiratory interventions

Physiotherapy

  • Children with neuromuscular weakness have difficulty clearing respiratory secretions and have a tendency to develop atelectasis of the lung bases. Both problems predispose to respiratory infections, which, in turn, stimulate more mucus production.

  • The main reason for both problems is the inability to take deep breaths to fully expand the lungs and to generate sufficient volume for an effective cough. Weakness of the expiratory muscles and muscles of the glottis also contribute to an ineffective coughing.

  • Augmented cough methods are a key part of an effective airway clearance and consist of augmentation of inspiration and assisted expiration.

  • The priority is to increase the inspired volume, and this can be augmented manually with a bag–valve mask system or mechanically with either a ventilator or a cough-assist machine. Breath-stacking and glossopharyngeal or ‘frog’ breathing, in which the glossopharyngeal muscles are used to push air into the lungs, can also be used to augment lung volumes in motivated older children.

  • Assistance with coughing can be achieved manually by compression of the upper abdomen or chest wall at the same time as the child tries to cough (manual assisted coughing). Cough assistance can also be achieved mechanically, using an increasing range of cough-assist devices (mechanical insufflation/exsufflation).These devices have not been evaluated in RCTs, but they appear to be a very useful addition to secretion clearance techniques, particularly during infective exacerbations.

  • Assisted lung insufflation and exsufflation can be combined with standard chest physiotherapy to assist with secretion clearance.

  • All children with an ineffective cough should be taught augmented cough techniques and have access to a system that they and their families can use.

  • Airway clearance techniques should be used during respiratory infections, and, if they fail to result in an oxygen saturation of 95% or above in room air, then hospital treatment is needed.

Antibiotics and vaccination

  • Early and aggressive use of antibiotics in children with neuromuscular weakness who develop respiratory signs seems sensible. In children with recurrent respiratory exacerbations, particularly during winter, daily prophylactic antibiotics are sometimes used, although there is no objective evidence of benefit.

  • As for all children at risk of respiratory infections, children with neuromuscular disease should be immunized against Pneumococcus and annually against influenza.

Ventilatory support

  • The aims of introducing NIV are to:

    • treat the symptoms of daytime or night-time hypoventilation and improve the quality of life;

    • reduce the frequency and impact of respiratory infections;

    • improve survival.

  • Criteria for starting NIV are not well established. In infants with severe weakness and frank respiratory failure, respiratory support is clearly needed if the child is to survive. In older children who develop night-time hypoventilation, the decision is less clear-cut.

  • There is no evidence that ‘prophylactic’ NIV improves the quality of life or length of survival. Where there are no symptoms of hypoventilation and the child perceives no benefit of the NIV, it is generally poorly tolerated and little used by the child.

  • It is not known whether an early use of NIV in younger children with neuromuscular weakness may have a beneficial effect on lung growth by promoting lung expansion, but it may be effective in preventing chest wall deformity. It is not known whether, where there is mild asymptomatic night-time hypoventilation, NIV would improve cognitive development.

  • When there is documented daytime hypercapnia, there is evidence of improved survival if NIV is introduced, at least in boys with DMD.

  • When there is evidence of nocturnal hypoventilation, but daytime normocapnia, the decision to introduce NIV depends on:

    • the presence of symptoms of hypoventilation (but note that children with neuromuscular weakness may underestimate their symptoms, particularly those of daytime fatigue, and that these may only become recognized in retrospect, after NIV has been started);

    • the occurrence of troublesome recurrent respiratory infections;

    • the nature of the neuromuscular weakness (for progressive conditions, like DMD, daytime hypercapnia will inevitably follow night-time hypoventilation, usually within 2–4 years);

    • whether scoliosis surgery is planned (children with neuromuscular weakness often require NIV support after extubation, and this is much easier to provide if the NIV has been introduced preoperatively).

  • When there is symptomatic daytime hypercapnia, a choice between NIV and ventilation via a tracheostomy tube also needs to be made. There are proponents of each approach.

    • NIV via a nasal mask cannot usually be used continuously, because pressure from the mask will result in breakdown of the facial skin. Other methods of augmenting daytime breathing can be introduced in older motivated children, such as glossopharyngeal breathing and on-demand mouthpiece ventilators, which are usually attached to wheelchairs with a mouthpiece that the child can easily reach.

    • Tracheostomy is an alternative and has the advantage of being away from the face and, at least in theory, easier to use. The use of a speaking valve allows speech during ventilation, although speech will invariably be affected to some extent. Disadvantages include adverse effects on swallowing, an increased risk of infection, and troublesome secretions requiring frequent suctioning. The cosmetic appearance of a tracheostomy is also distressing to many children and their families. There may also be more difficulty in getting a child placed at school if they have a tracheostomy.

  • Daytime ventilation improves symptoms of dyspnoea, fatigue, and headaches, and it improves survival.

Nutrition

  • Good nutrition is essential to maximize muscle development.

  • Weak children often have incoordinate swallowing movements and are prone to GOR.

  • Adequate nutrition may require the use of gastrostomy feeding. If a gastrostomy is needed, performing a fundoplication at the same time should be carefully considered.

  • Excessive weight gain should be avoided to prevent unnecessary respiratory work.

Management in the intensive care unit

Ventilation strategy

  • Despite careful attention to physiotherapy and secretion clearance, some children with respiratory weakness will have exacerbations leading to respiratory failure that cannot be managed using NIV, usually because of increasing oxygen requirements associated with areas of lung collapse.

  • Most experience of ventilating weak children with successful outcomes has been reported by Bach et al. who describe a successful protocol that has been evaluated in a retrospective study.1 The protocol emphasizes the following points, once a child is intubated and ventilated:

    • aim for saturations of around 95%;

    • use a positive end-expiratory pressure (PEEP) of 3–5 cmH2O;

    • use a cough-assist device via the ETT to aid the clearance of secretions;

    • maintain the inspiratory pressure to provide adequate minute volumes, and only wean inspired oxygen as the child improves;

    • do not attempt extubation, until the child is ventilated in air, the requirement of suction is not more than 6-hourly, any fever has resolved, and any nasal secretions have dried up;

    • extubate to nasal ventilation, in air, using the cough-assist device to treat desaturations (typical ventilator settings would be 15–20 cmH2O peak and 3–5 cmH2O PEEP);

    • repeated or prolonged desaturation is an indication for re-intubation.

Using this regime, Bach et al. report successful extubation (not requiring re-intubation during the same hospital admission) of around 80%. The likely duration of intubation is around 8–10 days.

  • If a negative pressure jacket ventilator is available, this can be a useful adjunct after extubation, allowing time off NIV, whilst still providing some respiratory support.

  • A nasopharyngeal airway can be left in situ after extubation to allow suction catheters to be passed to the posterior nasopharynx with minimum discomfort.

Ethical aspects of care

The approach to the care of children with severe muscle weakness, particularly those children requiring full-time ventilation, is controversial. The position of most UK units has been published2 and can be summarized as follows.

  • The family should be given all relevant information about the likely outcome and possible interventions.

  • Personal views of the medical team should not be used to judge the child’s likely quality of life. Children with neuromuscular weakness rate their quality of life at a much higher level than some health care workers might imagine and, in some cases, no different from that of healthy age-matched children.

  • If the family of a very weak child with respiratory failure opts for ventilatory support, a reasonable plan would be to:

    • use non-invasive positive pressure ventilation (NIPPV) overnight and also for daytime rescue periods during respiratory infections;

    • provide full physiotherapy support, including cough-assist manoeuvres;

    • provide short-term intensive care, including periods of intubation for severe exacerbations;

    • if this is insufficient to support the child because they have daytime respiratory failure, even when ‘well’, most units in the UK would recommend palliative care, rather than a tracheostomy, and full-time ventilatory support in children with severe generalized weakness. Older children may manage without a tracheostomy, using a regime of glossopharyngeal breathing or the use of on-demand ‘sip’ ventilators.

  • Placing a tracheostomy in a very weak child can result in complete ventilator dependence in a child who previously had some respiratory drive. This may reflect the loss of ability to maintain residual volume or the difficulties in dealing with secretions from the tracheostomy.

  • If the parents of very weak infants opt for palliative care from the outset, this position can be supported in good faith. To avoid undue distress because of CO2 retention, NIPPV can be initiated and used during the night and for short periods during the day. Intensive physiotherapy regimes and intubation would not be appropriate in this setting.

  • Families may alter their views about what they want for their child, and they must be allowed to do so.

Further information

Fauroux B, Lofaso F (2005). Non-invasive mechanical ventilation: when to start for what benefit? Thorax 60, 979–80.Find this resource:

Hull J, Aniapravan R, Chan E, et al. (2012). British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax 67 (Suppl. 1), i1–40.Find this resource:

Spinal muscular atrophy

  • SMA is an autosomal recessive condition characterized by proximal muscle weakness caused by the primary degeneration of the anterior horn cells of the spinal cord, and often of the bulbar motor nuclei, without evidence of primary peripheral nerve or long tract involvement.

  • It has an incidence of 1/10 000 live births, with a carrier frequency of approximately 1 in 50.

  • Atypical forms of the disease have been described, including those with associated sensory deficits, hearing loss, arthrogryposis, and bone fractures. Some of these forms may be X-linked and unrelated to the SMN1 gene defect. SMA with respiratory distress (SMARD) is a distinct condition and is described later in the chapter.

  • SMA is caused by mutations in SMN1 (survival of motor neuron) gene, nearly always a large deletion, usually of the entire gene. Rare point mutations are also described. The adjacent SMN2 genes are nearly identical to SMN1 but differ by one base in exon 7. This base change results in exon 7 being skipped in a high proportion of SMN2 transcripts, with the formation of a truncated protein product. This means that, although some SMN protein is made from the SMN2 gene, this does not fully compensate for the loss of SMN1 function. The loss of both SMN1 and SMN2 genes causes embryonic death.

  • The disease severity in SMA correlates with the SMN2 copy number; this varies from one to four copies.

  • SMN1 is expressed in all tissues but appears to have effects only on motor neurons. SMN protein is involved in ribosome formation and in transporting messenger ribonucleic acid (mRNA) in axons.

  • SMA is divided into three types, according to the age of onset and clinical severity.

    • Type 1: muscle weakness (predominantly proximal) and hypotonia usually in the first few weeks of life and always before 6 months of age. These children are never strong enough to sit. Respiratory failure (at least during sleep) occurs before 2 years of age. Type 1 can be subdivided into ‘true type 1’ and intermediate type 1. True type 1s present in the first 3 months of life, and, by the age of 18 months, they will be left with only residual finger, toe, and facial movements. The majority will have had one acute episode of respiratory failure requiring intubation. Intermediate type 1s present between 3 and 6 months of age and will be able to raise their heads off the bed, although they never sit. When these children are older, they will be able to operate electric wheelchairs and talk.

    • Type 2: onset of weakness before 18 months of age. Able to sit but not walk. May become weaker, so that the ability to sit is lost after 1–2 years.

    • Type 3: onset of weakness after the age of 2 years. Initially able to walk. May become weaker, so that the ability to walk is lost after a variable period.

    • Usually, the diagnosis will have already been made before a respiratory opinion is sought. Occasionally, a weak infant with respiratory distress will be referred first to a respiratory paediatrician. The following signs suggest SMA type 1.

    • Hypotonia and proximal weakness lead to a frog-like posture.

    • The cry is often weak.

    • Tendon reflexes are absent.

    • Contractures are rare.

    • There may be fasciculations of the tongue.

    • The chest may be bell-shaped.

    • There is preservation of the diaphragm and weakness of the intercostal muscles. This means that, on inspiration, the abdomen moves out, but there is intercostal recession and limited chest expansion. Infants with weakness in utero may also have small-volume lungs.

  • Progression of weakness is inevitable, but the degree of progression is variable. Children who develop respiratory failure will usually have type 1 disease or the weaker end of type 2 who have lost the ability to sit. Most of the children with type 2 disease and intermediate type 1 disease are able to operate an electronic wheelchair and to sit with special supports. Most are also able to talk, and some will be able to feed orally. They have a normal intellectual development.

  • Some children with SMA will require intubation and ventilation during respiratory infections. These tend to become less frequent with age and are relatively unusual after 5 years of age. Long-term survival in children with SMA type 1, supported either by non-invasive or tracheostomy support, is now described.

  • Children with SMA are prone to lactic acidosis during periods of illness or fasting. Whether there are metabolic abnormalities caused by an underlying defect associated with SMA is not known. Underweight patients with SMA with minimum muscle mass may be at risk of recurrent hypoglycaemia or ketosis, although patients typically recover in 2–4 days. The acidosis will make the child feel unwell and may induce vomiting. It will also drive respiration. It should be treated with NG feeds or IV dextrose, depending on how unwell the child is at the time. Bicarbonate should be avoided, as it will cause elevation of CO2.

Spinal muscular atrophy with respiratory distress

  • SMARD (also known as diaphragmatic spinal muscular atrophy, distal hereditary motor neuronopathy type VI, and severe infantile axonal neuropathy with respiratory failure) is an autosomal recessive condition caused by mutations in the immunoglobulin-binding protein 2 (IGHMBP2) gene.

  • As with SMA, there is loss of α‎-motor neurons in the anterior horn of the spinal cord, leading to neurogenic muscular atrophy, with subsequent symmetrical muscle weakness of the trunk and limbs.

  • In contrast to SMA, the distal, rather than proximal, muscles, are more severely affected in SMARD, and diaphragm weakness is invariable and early (in SMA, the intercostal muscles are weak, with a relative preservation of the diaphragm).

  • All infants with SMARD will require full-time respiratory support to survive, almost always within the first year of life.

  • There may be deformities of the feet and/or contractures of the fingers.

  • Infants with SMARD may present at birth or as late as 6 months of age. In some infants, the first presentation may be with respiratory failure, before any limb weakness is noticed.

  • Weakness rapidly progresses in the first year of life and becomes generalized, eventually affecting the upper and lower limbs and trunk.

  • After the first year, progression slows, and any residual power tends to be preserved.

  • Sensory and autonomic dysfunction can also occur.

  • The inevitable requirement for full-time respiratory support—almost always via a tracheostomy—needs to be explained to families when decisions are being made about the best course of management.

Treatment and outcome

  • Management, as with all children with neuromuscular weakness, starts with fully informing the family of the problems the child has and is likely to face.

  • Attention to physiotherapy, nutrition, swallowing, GOR, and respiratory support will be needed, as discussed.

  • The outcome depends, to some extent, on the level of intervention the family and medical team think is appropriate. Even with full support, children with true type 1 SMA are at risk of death from sudden-onset respiratory failure, usually associated with respiratory infection.

Further information

Bach JR, Niranjan V, Weaver B (2000). Spinal muscular atrophy type 1: a noninvasive respiratory management approach. Chest 117, 1100–5.Find this resource:

Kaindl AM, Guenther UP, Rudnik-Schöneborn S, et al. (2008). Spinal muscular atrophy with respiratory distress type 1 (SMARD1). J Child Neurol 23, 199–204.Find this resource:

Nurputra DK, Lai PS, Harahap NI, et al. (2013). Spinal muscular atrophy: from gene discovery to clinical trials. Ann Hum Genet 77, 435–63.Find this resource:

    Duchenne muscular dystrophy

    Clinical features

    • Inheritance is X-linked recessive. Mapping and molecular genetic studies indicate that DMD and Becker muscular dystrophy (BMD) both result from mutations in the dystrophin gene and may be considered together, using the term Xp21 dystrophy. Two-thirds of the mutations are deletions. Although there is no clear correlation found between the extent of the deletion and the severity of the disorder, in DMD, 96% of deletions result in a shift in the amino acid reading frame (frameshift mutations), which inevitably results in the loss of protein function. In BMD, 70% of mutations are in-frame; 30% of mutations in DMD arise de novo.

    • The onset is most commonly at the age of 3–5 years, manifest as symmetrical weakness more marked proximally, and is more marked in the lower than upper limbs. Pseudohypertrophy, due to muscle fibrosis, is usually most marked in the calf muscles and can be progressive.

    • The motor function is reduced within 2–3 years of diagnosis, with a steady decline in strength beginning 6–11 years later. The ability to walk is usually lost by 9–13 years.

    • Obesity, muscle contractures, dilated cardiomyopathy (after the age of 15), night blindness, and learning difficulties (mean IQ 88) are other common problems.

    • Scoliosis usually follows the loss of ambulation. The onset may be delayed if walking and standing are prolonged. Surgical insertion of a spinal rod may be required. The timing of surgery is crucial. Where possible, it should be undertaken when the lung function is relatively preserved, in order to lessen the anaesthetic risk. A degree of correction by surgical means facilitates sitting and may lessen the degree of restrictive lung function that inevitably develops.

    Diagnosis

    Typical clinical picture, plus:

    • elevated creatine kinase;

    • myopathic muscle biopsy.

    Treatment and outcome

    • The use of long-term oral corticosteroids has altered the natural history of this disease and preserved functional capabilities and pulmonary function, delaying the need for respiratory support. Various corticosteroid regimes are used to minimize the side effects.

    • Before the use of corticosteroids and without respiratory support, death occurred between 15 and 25 years of age, usually from respiratory failure. With respiratory support, life can be prolonged by several years, although weakness continues to progress. Respiratory support is first needed at night-time only. With progressive weakness, daytime support will be required, either via a tracheostomy or by using sip ventilation, with or without glossopharyngeal breathing techniques.

    • A regular chest physiotherapy regime is required to clear respiratory secretions. Cough-assist devices may be helpful.

    Further information

    Toussaint M, Steens M, Wasteels G, Soudon P (2006). Diurnal ventilation via mouthpiece: survival in end-stage Duchenne patients. Eur Respir J 28, 549–55.Find this resource:

    Congenital muscular dystrophies

    A group of at least 20 autosomal recessive disorders, characterized by the following.

    • Generalized weakness and hypotonia, usually from birth and always within the first year of life.

    • Contractures—frequently present.

    • Elevated serum creatinine kinase in most.

    • Myopathic changes on muscle biopsy:

      • fibre size variation;

      • increased connective tissue or fat.

    • CNS involvement, with evidence of developmental delay, may be present.

    • Several different structural genes (e.g. merosin, fukutin) and enzymes (e.g. o-mannosyltransferase) are involved in these diseases. The severity varies. The more severe conditions are associated with progressive deterioration, with eventual respiratory failure. In others, weakness is mild, and no progression is seen.

    • Selenoprotein N1 (SEPN1) mutations are associated with the development of a rigid spine and axial weakness—congenital muscular dystrophy with early rigid spine. SEPN1 mutations are also found in children with minicore structural myopathy.

    • Rigid spine syndrome (RSS) was first proposed by Dubowitz in the 1970s to describe a condition resembling muscular dystrophy, with onset in infancy, but a relatively benign course of muscle weakness, associated with early and severe spinal and limb joint contractures. Nocturnal hypoventilation can be an early feature and a cause of mortality. Early spinal rigidity can also be found in some of the congenital myopathies (see Neuromuscular weakness ‘Congenital structural myopathies’, p. [link]). It is important to recognize that these children can develop severe night-time hypoventilation, despite an FEV1 of >60% and reasonable limb strength, including the ability to walk.

    Further information

    Neuromuscular Disease Center at Washington University, St. Louis, USA. Available at: <http://neuromuscular.wustl.edu/>.

    Myotonic dystrophy

    • Inheritance is autosomal dominant.

    • The incidence is around 14/100 000 live births.

    • The disease is caused by a CTG expansion in the 3´ untranslated region of the dystrophia myotonica protein kinase gene. The mechanism by which the expansion leads to disease is poorly understood, but the abnormal mRNA derived from the expanded gene appears to affect the expression and splicing of several other genes, possibly by sequestering transcription factors.

    • The disease severity depends upon the number of CTG repeats, which can vary within families, and is typically worse in offspring (genetic anticipation).

      • Mildly affected: 50–150 repeats.

      • Classic disease range: 100–1000 repeats.

      • Severely affected (usually congenital presentation): 1000–5000 repeats.

    Clinical features

    • The age at onset varies from birth to adulthood.

    • Childhood forms are usually, but not always, associated with developmental delay.

    • Myotonia is not usually detectable in young children.

    • The severe neonatal form of the disease is most likely to be associated with respiratory impairment.

    • Older children with myotonic dystrophy can develop hypoventilation, which may be exacerbated by a reduced response to hypoxia.

    • Affected neonates usually have more mildly affected mothers, in whom myotonia can be demonstrated (e.g. by a delayed release of the grip after a handshake). Neonates with myotonic dystrophy usually have:

      • marked hypotonia;

      • generalized weakness, including the face;

      • typical facial appearance with a triangular open mouth;

      • talipes and other contractures;

      • respiratory failure is common, and respiratory support may be required.

    • Other problems in later life include:

      • cataracts;

      • heart rhythm disturbance;

      • oesophageal dysfunction;

      • hypogonadism.

    Investigations

    • Electromyography (EMG) in the mother (or, more rarely, the father) usually shows myotonia, and the serum creatinine kinase is usually elevated.

    • Serum creatinine kinase often normal.

    • EMG may be normal.

    • Muscle biopsy often normal.

    • Head MRI may show enlarged ventricles, with central white matter changes.

    • Genetic tests show CTG expansion of the DMPK gene.

    Treatment and outcome

    • Treatment is supportive.

    • In older childhood, myotonia can be troublesome and be helped by drug treatment, e.g. with procainamide.

    • Although prolonged neonatal ventilation (>30 days) may be needed, most infants can be weaned onto night-time support by nasal mask or off ventilation completely.

    • There is an apparent improvement over the first decade, and most affected infants will be able to walk. There may be increased weakness in the second decade, with the appearance of myotonia. Most children will have cognitive impairment requiring special schooling.

    • Those already on ventilatory support as infants should have their need for support reviewed 6–12-monthly. Older children with worsening weakness should have an annual assessment, usually by night-time PSG.

    Further information

    Campbell C, Sherlock R, Jacob P, Blayney M (2004). Congenital myotonic dystrophy: assisted ventilation duration and outcome. Pediatrics 113, 811–16.Find this resource:

    Congenital structural myopathies

    • In children with congenital structural myopathies, the serum creatinine kinase is often normal or only minimally elevated, and the diagnosis is made on the striking structural abnormalities in the muscle fibres.

    • These disorders are usually present at birth but may not be noticed until later childhood.

    • Most are mild and non-progressive; some are severe.

    • Joint contractures and arthrogryposis can occur.

    • Inheritance is usually autosomal dominant. Autosomal recessive forms are usually more severe.

    Clinical features

    • Generalized weakness.

    • Muscle wasting.

    • Delayed motor development.

    • Joint contractures.

    Investigations

    • Creatinine kinase normal or marginally elevated.

    • EMG: myopathic picture (brief, small amplitude, polyphasic potentials).

    • Muscle biopsy appearance is diagnostic.

    Specific conditions

    • Central core:

      • non-progessive; usually mild, although can be severe; the severity can vary within families;

      • normal intellect;

      • caused by mutations in the ryanodine receptor gene;

      • can be associated with malignant hyperthermia.

    • Minicore (multicore):

      • proximal, moderate, non-progressive weakness; occasionally severe;

      • normal intellect;

      • several possible genetic causes, including ryanodine receptor and selenoprotein N1 (SEPN1) gene mutations. SEPN1 mutations can be associated with a rigid spine and early respiratory compromise.

    • Nemaline:

      • can be autosomal dominant or recessive;

      • recessive form is severe and presents in early life with weakness, marked hypotonia, and respiratory failure;

      • usually due to mutations in alpha-actin; other proteins (nebulin, troponin) can be involved;

      • may be associated with pectus carinatum and pes cavus.

    • Myotubular or centronuclear:

      • The dominant form (dynamin or MYF6 gene mutations) is usually mild;

      • X-linked recessive and autosomal recessive forms (myotubularin gene mutations) are severe.

      • Congenital fibre-type disproportion:

      • usually type 1 and type 2 fibres are similar in size; variation is seen in several conditions, but, where type 1 fibres are smaller than type 2, congenital fibre-type disproportion is likely;

      • non-progressive;

      • the severity varies;

      • may be associated with a short stature and foot deformities.

    Treatment

    Treatment is supportive. Respiratory support may be needed in the more severe forms.

    Glycogen storage disease type II (Pompe disease)

    • Although some weakness may be seen with types III and V glycogen storage disease, marked weakness and an associated respiratory failure are most frequent in Pompe disease.

    • Pompe disease is a rare (the incidence is 1/40 000) autosomal recessive disorder, caused by mutations in the acid alpha-glucosidase gene. Acid alpha-glucosidase is a lysosomal enzyme required for the metabolism of a minor fraction (1–3%) of glycogen stores. Reduced activity does not lead to hypoglycaemia, but an accumulation of glycogen in lysosomes and the cytoplasm leads to cellular injury, particularly in muscle tissue.

    • There are three forms of the disease, depending on the level of residual acid alpha-glucosidase activity.

      • Infantile: severe, with cardiac involvement (hypertrophic cardiomyopathy).

      • Juvenile: presentation after the first year of life; no cardiac involvement.

      • Adult onset: presentation in the second decade or later. Often, relatively mild proximal limb weakness, but at least 30% will develop respiratory failure.

    • The infantile form presents in the first few months of life, with hypotonia, weakness, and cardiac failure. It can resemble SMA type 1, and infants with Pompe never sit unaided. Without treatment, death usually occurs in the first year of life from cardiorespiratory failure.

    • Older children present with slowly progressive proximal muscle weakness, following a normal early motor development. The juvenile form progresses at a variable rate, and, without treatment, children become confined to wheelchairs. Death usually occurs in the second or third decade from respiratory failure. The adult-onset form can be stable over a number of decades.

    • Examination findings are those of hypotonia and muscle weakness. In the infantile form, there is moderate hepatomegaly (in 80%) and macroglossia (in 60%). In older children, these features are usually absent.

    • Diagnosis is by EMG (myopathic pattern), muscle biopsy (myopathy with glycogen deposits), and leucocyte or fibroblast culture for acid alpha-glucosidase activity. Genetic analysis may help, although rare mutations will not be detected. A blood film may show lymphocytes with glycogen-containing cytoplasmic vacuoles.

    • Enzyme replacement therapy has shown some dramatic beneficial effects and has become an established treatment, but it has side effects and significant cost implications, and long-term outcomes are uncertain.

    Respiratory problems

    • The diaphragm is weak in children with Pompe disease, and the problems these children have are the same as those of any child with weakness of the respiratory muscles:

      • a weak cough and the consequent risk of both recurrent and severe LRTIs and aspiration;

      • night-time and daytime hypoventilation with associated symptoms.

    • Infants with Pompe disease are at an increased risk of left lower lobe collapse, as a result of compression of the left lower lobe bronchus by the often massively enlarged heart.

    • PSG should be carried out to determine the presence and severity of any night-time hypoventilation.

    • Respiratory support, using NIV and cough-assist manoeuvres, can reduce symptoms and improve the quality of life in these children. Replacement enzyme therapy is changing the natural history.

    Further information

    Angelini C, Nascimbeni AC, Semplicini C (2013). Therapeutic advances in the management of Pompe disease and other metabolic myopathies. Ther Adv Neurol Disord 6, 311–21.Find this resource:

    Van den Hout JM, Kamphoven JH, Winkel LP, et al. (2004). Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics 113, e448–57.Find this resource:

    Myasthenic syndromes

    • The common adult form of autoimmune MG is defined by fluctuating muscle weakness, as a result of antibodies directed against the acetylcholine receptor (AChR) of the neuromuscular junction synapses. This form of myasthenia can start in the second decade of life (juvenile MG). Respiratory failure is rare, although it can occur during myasthenic crises.

    • Respiratory problems, as a result of myasthenia, are more often associated with infants or young children who have severe generalized weakness. This group of children is likely to have one of a larger number of congenital or familial disorders of the neuromuscular junction, rather than an autoimmune disease. All of these disorders cause weakness, but not all are fluctuating or show fatiguability.

    • Neonatal myasthenia, caused by transplacental transfer of anti-AChR antibodies, is seen in 10–30% of infants of mothers with autoimmune MG. Generalized weakness and respiratory failure are typical. The diagnosis is made by confirming MG in the mother, detecting anti-AChR antibodies in the affected neonate, and demonstrating an objective improvement in symptoms when anticholinesterase inhibitors are administered. Treatment is with either pyridostigmine or neostigmine, with supportive management (including ventilation, adequate nutrition), as required, until natural remission occurs. Symptoms usually subside over 1–4 weeks.

    Congenital and familial myasthenic syndromes

    These disorders can be classified as follows.

    • Pre-synaptic—accounts for 10% of cases.

      • Defects in the synthesis of acetylcholine (ACh), caused by mutations in the choline acetyl transferase (ChAT) enzyme and consequently insufficient ACh available in the synapse. This condition is sometimes called ‘myasthenia gravis and episodic apnoea’.

      • Defects in the release of ACh.

    • Synaptic—accounts for 15% of cases.

      • Defects in acetylcholinesterase (AChE). This prevents the rapid degradation of ACh, resulting in a depolarizing block. In these children, giving AChE inhibitors, such as IV edrophonium chloride (Tensilon® test), can cause deterioration and respiratory failure by further increasing synaptic ACh and worsening the depolarizing block.

    • Post-synaptic—accounts for 75% of cases.

      • Most are caused by mutations in the subunits of the AChR.

      • Others are caused by mutations in other synaptic proteins such as rapsyn, dok-7, or plectin (which also causes epidermolysis).

    Clinical features

    • Myasthenic syndromes can present at any age, from birth to adulthood, but usually there will be evidence of weakness at birth or in infancy.

    • Weakness may be ocular, bulbar, or generalized.

    • Typically, there is fluctuation in the severity, but this is not always present. Fluctuation is particularly marked in ChAT deficiency. These infants may have severe deteriorations requiring ventilatory support, between which they can be apparently normal.

    • Most forms can cause respiratory failure.

    • Arthrogryposis (fixed flexion deformities of the limbs) may be present.

    Investigations

    • AChE inhibitors (edrophonium IV over 1 min or neostigmine IM) will result in some improvement in pre-synaptic and most post-synaptic conditions, although the response is often incomplete. In AChE deficiency, giving AChE inhibitors leads to deterioration. An increase in muscle strength, after AChE inhibitors have been given, is not specific for myasthenic conditions.

    • Antibodies against ACh will be absent.

    • EMG may show suggestive abnormalities and typically will show a decrement of the muscle action potential on repetitive testing, as the pre-synaptic ACh is exhausted.

    • Muscle biopsy with staining for AChR may help with the diagnosis.

    • Genetic tests looking for mutations in specific proteins may be diagnostic and provide some prognostic information.

    Treatment and outcome

    • Children with respiratory failure, even if intermittent, should be commenced on non-invasive BIPAP. This will typically be needed at night-time to prevent unforeseen respiratory compromise during the night. During the day, when the child can be more easily observed, BIPAP may be used, as needed. Weakness may become worse during an intercurrent illness, and it is important that the child and family are familiar with a BIPAP system for use when needed.

    • Anti-AChE medication is usually tried in all children. It will not be effective in AChE deficiency and often is only partially effective or ineffective in AChR defects.

    • 3,4-diaminopyridine or quinidine may be helpful in AChR defects.

    • Ephedrine and salbutamol may help in AChE deficiency.

    • The prognosis is variable. Some children show improvement with age, and even those with respiratory failure in infancy may become strong enough to walk. Other children show progression, and some are severely disabled. The nature of the defect has some impact on severity, but, even within each separate condition, a wide variation in severity and disease progression is observed.

    Guillain–Barré syndrome

    • GBS is an immune-mediated acute demyelinating polyneuropathy that may occur at any age.

    • The incidence in children is 0.5–1.5 in 100 000.

    Clinical features

    • There may be a prodromal viral illness, followed 10–14 days later by generalized symmetrical weakness of acute onset, usually starting in the lower extremities and extending proximally.

    • The respiratory muscles and those supplied by the cranial nerves may be affected. Bulbar dysfunction and difficulty swallowing may lead to aspiration and respiratory arrest.

    • Pain and paraesthesiae in the lower limbs or back occur in up to 60% of affected children.

    • Bladder dysfunction can occur.

    • Headache, meningism (30%), and ataxia are not uncommon.

    • Papilloedema occurs in <5%.

    • Mental clarity is usually fully preserved.

    • Autonomic dysfunction (labile heart rate and blood pressure) occurs in up to 40% of affected children.

    Diagnosis

    The diagnosis is usually made on clinical grounds. Supportive laboratory investigations include:

    • high CSF protein (elevated in 65% of cases in the first week, 80% in the second week);

    • CSF oligoclonal bands (10–30%);

    • nerve conduction studies suggestive of demyelination.

    Respiratory aspects of management

    Approximately 15% of affected children develop respiratory failure. The likelihood of the need for mechanical ventilation is difficult to predict. It may be required in the following settings.

    • A rapidly ascending weakness may affect the respiratory muscle function (intercostal muscles, diaphragm), resulting in hypoventilation and ultimately respiratory failure. Sequential pulmonary function testing in children aged 5 years or more can be useful in indicating the degree of hypoventilation and in tracking its severity. A low VC of <20 mL/kg or a decrease of >30% from the baseline are generally indicative of a need for invasive or non-invasive respiratory support.

    • Bulbar dysfunction, with a loss of the normal protective upper airway reflexes.

    • The presence of bilateral facial weakness has been reported by some groups as a marker of an impending respiratory failure.

    • Severe dysautonomia (cardiac arrhythmias, blood pressure lability).

    Although, in adult studies, the duration of ventilator use and pulmonary morbidity are not increased in patients who required emergency intubation, when compared with those intubated semi-electively, it is clearly preferable not to have an uncontrolled respiratory arrest on a general paediatric ward.

    Prognosis

    • Mortality is extremely low, with cardiac arrhythmias the commonest cause of death.

    • The long-term neurological outcome is generally good, though minor residual deficits are relatively common.

    • The outcome after mechanical ventilation is usually good, though a prolonged period of ventilation (with tracheostomy) may be required. The median duration of ventilation is around 21 days.

    • Once extubated, a period of NIV may be required, until sufficient strength has been regained. Once safely established, this can be continued at home, provided an adequate support network is in place.

    • Gastrostomy feeding may be required in severe cases where the length of recovery is protracted.

    • The expectation is for full recovery, with no requirement for long-term support.

    • Lung function testing after recovery is normal.

    Further information

    Bach JR, Niranjan V, Weaver B (2000). Spinal muscular atrophy type 1: a noninvasive respiratory management approach. Chest 117, 1100–5.Find this resource:

    Burke G, Hiscock A, Klein A, et al. (2013). Salbutamol benefits children with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord 23, 170–5.Find this resource:

    Bush A, Fraser J, Jardine E, Paton J, Simonds A, Wallis C (2005). Respiratory management of the infant with type 1 spinal muscular atrophy. Arch Dis Child 90, 709–11.Find this resource:

    Campbell C, Sherlock R, Jacob P, Blayney M (2004). Congenital myotonic dystrophy: assisted ventilation duration and outcome. Pediatrics 113, 811–16.Find this resource:

    Fauroux B, Lofaso F (2005). Non-invasive mechanical ventilation: when to start for what benefit? Thorax 60, 979–80.Find this resource:

    Finnis MF, Jayawant S (2011). Juvenile myasthenia gravis: a paediatric perspective. Autoimmune Dis 2011, 404101.Find this resource:

    Grohmann K, Varon R, Stolz P, et al. (2003). Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol 54, 719–24.Find this resource:

    Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF (2001). Anticipating mechanical ventilation in GBS. Arch Neurol 58, 893–8.Find this resource:

    Neuromuscular Disease Center at Washington University, St. Louis, USA. Available at: <http://neuromuscular.wustl.edu/>.

    Ryan MM (2013). Pediatric Guillain-Barré syndrome. Curr Opin Pediatr 25, 689–93.Find this resource:

    Sladky JT (2004). Guillain Barre syndrome in children. J Child Neurol 19, 191–200.Find this resource:

    Toussaint M, Steens M, Wasteels G, Soudon P (2006). Diurnal ventilation via mouthpiece: survival in end-stage Duchenne patients. Eur Respir J 28, 549–55.Find this resource:

    Van den Hout JM, Kamphoven JH, Winkel LP, et al. (2004). Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics 113, e448–57.Find this resource:

    Wijdicks EM, Henderson RD, McClelland RL (2003). Emergency intubation for respiratory failure in GBS. Arch Neurol 60, 947–8.Find this resource:

    Notes:

    1 Bach JR, Niranjan V, Weaver B (2000). Spinal muscular atrophy type 1: a noninvasive respiratory management approach. Chest 117, 1100–5.

    2 Bush A, Fraser J, Jardine E, Paton J, Simonds A, Wallis C (2005). Respiratory management of the infant with type 1 spinal muscular atrophy. Arch Dis Child 90, 709–11.