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Neuromuscular Disorders

The term ‘neuromuscular disorder’ is used to describe any disease with the primary pathology arising in the lower motor tract and impacting on the functioning of muscles. This large collection of disorders encompasses disease of the anterior horn cells, peripheral nerves, neuromuscular junction (NMJ), and the muscles themselves.

 

Presentation

Neuromuscular Disorders

Patients can present at different ages, depending on the disease process in question.  Common presenting complaints are:

  • Floppiness – usually picked up in neonates.
  • Delayed motor milestones – usually picked up in infancy.
  • Weakness of a muscle/muscle group – picked up at any age.
  • Gait abnormality – picked up at any age.
  • Fatigability – picked up at any age.
  • Inability to keep up with peers – often picked up at school age.

 

A child may even present before they are born, if there is a family history of inherited neuromuscular disorders.

 

 

Investigations

Most symptoms of neuromuscular disease are very non-specific, and a careful and thorough history and examination must be performed.

 

Blood tests

A full work up should be performed because many different conditions can manifest as weakness, including endocrine disorders and electrolyte disturbance.

  • Full blood count
  • CRP
  • U&Es
  • Glucose
  • Calcium
  • Magnesium
  • LFTs
  • TFTs
  • Lactate
  • Arterial blood gas sampling

 

A creatine kinase (CK) level should also be done.  CK is an enzyme present in tissues that use a lot of energy, so is present in large quantities in the muscles.  Raised serum levels of CK indicates damage to the muscle, and so can help identify the site of the neuromuscular pathology.

  • Very high levels – muscular dystrophy
  • Mildly raised levels – myopathy, spinal muscular atrophy
  • Normal – NMJ or peripheral nerve abnormality

 

Neurophysiology

Nerve conduction studies can be used to identify the pathology causing peripheral neuron loss.

Electromyography, in which electrodes are placed into the muscle and action potentials are recorded, can help differentiate between disorders of neurological origin and those of muscular origin.

 

Muscle biopsy

Often provides a definitive diagnosis.

 

Nerve biopsy

90% of sampled nerves will regenerate, but it is rarely done.

 

DNA testing

Neurophysiology and biopsies are unpleasant for children, so are only performed if necessary.  Nowadays gene testing has become more common, especially if the clinician is able to narrow down the differential diagnosis.  Testing of family members is often performed, to allow proper genetic counselling and antenatal planning.

 

Neuroimaging

This is important in any child presenting with muscle weakness or delayed motor milestones, especially if other features such as learning disabilities are present.

 

Other tests

Many neuromuscular disorders are associated with other pathology, such as cardiomyopathy in muscular dystrophy, and thymomas in myasthenia gravis.  Antibody testing in suspected autoimmune processes will help characterise the disease.  The need for further tests will be guided by the diagnosis.

 

 

Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy is an autosomal recessive condition caused by a defect in the gene coding for the ‘Survival of Motor Neuron’ gene.  Degeneration of anterior horn cells in the spinal cord leads to progressive weakness and muscle atrophy, but the extent of impairment varies depending on the type of SMA in question.

 

Type 1 SMA presents in infancy (or even antenatally, with reduced foetal movements), and is the most severe form of SMA.  These children never gain head control or sit unaided, suffer from respiratory complications, and death usually occurs by one year of age.

 

Type 2 SMA presents slightly later, with failure to walk by the age of 18 months.  These children never stand or walk unaided, but are able to achieve the sitting position.  Respiratory complications also result.

 

Those children who manage to walk at some point in their life have Type 3 SMA.  However, they may later lose this ability.

 

 

Peripheral Neuropathy

Fastbleep also contains a dedicated (peripheral neuropathies article)

 

There are two mechanisms of nerve disease - axonal (loss of axons) and demyelinating (loss of myelin sheaths).  These produce different patterns on nerve conduction studies.  Axonal neuropathies will have normal conduction speed, but reduced response.  Demyelinating neuropathies will have reduced conduction speed, but a normal response.

 

There are also several terms you need to be aware of:

  • Mononeuropathy simplex – involvement of a single named nerve (e.g. Bell’s palsy, which is involvement of the cranial nerve VII).
  • Mononeuropathy multiplex – involvement of more than one named nerve, usually at random and with no anatomical or temporal correlation.
  • Polyneuropathy – numerous peripheral nerves involved at the same time, usually symmetrically.

 

 

Hereditary motor sensory neuropathies (HMSN)

This is a group of disorders affecting the peripheral nerves.  Motor involvement predominates, but there is also impairment in sensory (and sometimes autonomic) function.

 

HMSN I (previously known as Charcot-Marie-Tooth disease, or Peroneal Muscular Atrophy) is the most common, and is a favourite of OSCE examiners.  It is an autosomal dominant demylinating condition causing varying levels of disability, but 60% of patients have some deficit by the age of 10.  The main signs and symptoms are:

  • Progressive weakness and wasting of distal muscles (inverted champagne bottle-shaped legs)
  • Foot malformations e.g. pes cavus
  • Toe-walking due to loss of foot dorsiflexion
  • Reduced distal reflexes
  • Palpable, hypertrophied nerves
  • Sensory loss, primarily proprioception and vibration

 

The other six HMSN are much less common, but can produce very similar clinical pictures.

 

 

Guillain-Barré syndrome

Guillain-Barré syndrome or, more correctly, acute post-infectious polyneuropathy, does exactly what it says on the tin.  It is an acute disease, affecting numerous nerves, and presents a few weeks after an upper respiratory tract infection or gastroenteritis.  It is presumed to be caused by the production of a cross-reactive antibody that attacks the myelin sheaths.

 

The predominant symptom is muscle weakness, starting distally and progressing proximally, though there may be some minor sensory involvement.  Treatment is largely supportive, and timely respiratory and nutritional support is the key to full recovery (occurs in 95% of patients).

 

 

THE MYASTHENIAS

Juvenile Myasthenia

Most of you will have covered myasthenia gravis, the adult autoimmune condition, before.  In myasthenia gravis an auto-antibody is produced against the ACh receptors found on post-synaptic membranes of neuromuscular junctions.  When the antibody binds to the receptor it prevents ACh binding and activating the receptor, and so an action potential is not created in the muscle fibres.  This leads to muscle weakness, or myasthenia.

 

Juvenile myasthenia is similar to the adult disease, as it is an autoimmune-mediated process involving antibodies against the ACh receptor.  Patients experience worsening muscle weakness as the day goes on, as ACh stores are depleted trying to overcome the antibody blockade.  The primary muscles affected are the muscles of the face, causing ptosis, diplopia, difficulty chewing, loss of facial expressions and slurring of speech.  Limb weakness can also be experienced proximally.

 

There are four ways to treat juvenile myasthenia:

  1. Anticholinesterases e.g. neostigmine – reduce breakdown of ACh in the post-synaptic cleft.
  2. Immunosuppressive therapy e.g. prednisolone or azothiaprine – reduce auto-antibody production.
  3. Thymectomy – many sufferers will have a thymoma, and remission of disease can be produced by thymectomy.
  4. Plasma exchange – used when the patient is so unwell they require respiratory support (a myasthenic crisis).

 

 

Lambert-Eaton Syndrome

In Lambert-Eaton (or sometimes Eaton-Lambert) syndrome an auto-antibody is directed at calcium channels in the neuromuscular junction, rather than at the ACh receptor.  As such it produces muscle weakness similar to juvenile myasthenia, but with a few differences:

  • The main symptom is proximal muscle weakness, and some bulbar involvement.  The ocular muscles are rarely affected.
  • The muscle weakness is ‘surmountable’ rather than ‘fatigable’.  That is, with repeated movements the weakness will grow less.
  • Approximately 75% of people will have autonomic dysfunction and/or cerebellar ataxia.

 

Up to 70% of patients with Lambert-Eaton syndrome have a tumour, usually small cell carcinoma of the lung, and so can be considered a paraneoplastic disease.  In those without a tumour, certain HLA subtypes have been implicated, and the patient may be more predisposed to other autoimmune conditions.

 

 

Congenital Myasthenic Syndrome

This is an inherited disorder that produces effects similar to juvenile myasthenia but through a different mechanism.  It is caused by a variety of different mutations in the genes coding for crucial proteins involved in neuromuscular transmission.  As with all disorders caused by a variety of mutations the disease course is very different between individuals.  The treatment also varies, and so characterisation of the gene mutation is very important in these children.

 

 

THE MUSCULAR DYSTROPHIES

The muscular dystrophies are a group of inherited disorders characterised by progressive loss of muscle fibres and the supporting tissues.

 

 

Duchenne’s Muscular Dystrophy

Duchenne’s muscular dystrophy is the most common neuromuscular disorder, affecting around 1 in 3500 male births.  It is an X-linked recessive condition caused by a deletion affecting the gene coding for dystrophin, a key component of muscle fibre cell membranes.  Around two thirds of cases are inherited, and one third results from spontaneous mutation.  Female carriers are usually asymptomatic, though over half will have raised CK levels, and there is a very high incidence (around 50%) of myocardial disease.

 

Children with Duchenne’s will have initially normal motor development, with symptoms beginning to appear at around 18 months of age.  50% of patients fail to walk by 18 months, but the average age of diagnosis still remains around 5 years of age.  Other presenting complaints are abnormal waddling gait, toe walking, difficulty getting up from the floor (Gower's sign: patient must ‘walk’ their hands up their body due to lack of hip and thigh strength - see video here), frequent falls, and painless degeneration of the muscles.  On examination you may see the classic hypertrophic calf muscle.

 

Patients may also have mild cognitive impairment and language delay, and there is a higher incidence of epilepsy than the general population.  The progressive nature of Duchenne’s means children require wheelchairs by the age of 13, and death occurs by the age of 25 from respiratory complications or associated dilated cardiomyopathy.  The use of prednisolone can prolong independent ambulation by two years, and there are several experimental treatments in the pipeline.

 

Contrary to popular belief, females can have Duchenne’s muscular dystrophy, due to inactivation of the normal X chromosome.  Also, some individuals with Turner's (XO) can have the full clinical picture of Duchenne’s.

 

 

Becker’s Muscular Dystrophy

In Becker’s muscular dystrophy the gene mutation responsible leads to production of an altered but still slightly functional dystrophin protein.  As a result the disease is less severe than Duchenne’s, with onset of symptoms at around 10 years of age and loss of ability to walk in their late twenties.  Less than 50% are alive at 40 years.

 

 

Facio-scapulohumeral Muscular Dystrophy

Another exactly-what-it-says-on-the-tin disease, with involvement of the facial muscles, the shoulder girdle, and the paraspinal muscles.  It is a relatively common autosomal dominant condition, and has a spectrum of severity.  It is not associated with cardiomyopathy.

 

 

Congenital Muscular Dystrophies

This is a large collection of disorders which present at birth.  Babies are very hypotonic, and muscle contractures may be apparent even then.  These dystrophies have associations with cardiomyopathy and learning difficulties.

 

 

THE MYOPATHIES

Inflammatory Myopathies

Benign acute myositis is a post-viral condition with acute onset of pain and weakness of legs a few days following an URTI.  Recovery is within days.

 

Juvenile dermatomyositis is a connective tissue disease related to the adult polymyositis, and is thought to be caused by inflammatory vascular changes affecting the muscles and the skin.  Initially the patient experiences a prodromal period with fever and malaise, and then develops proximal muscle weakness.  The classic heliotrope/violaceous rash appears on the eyelids and extensor surfaces.  The mainstay of treatment is immunosuppression, usually with corticosteroids.

 

 

Metabolic Myopathies

Metabolic myopathies are numerous but very rare.  Perhaps the most well known is Pompe disease, which is an abnormality in glycogen metabolism.  Metabolic myopathies present either in infancy, with hypotonia, or in order children, with exercise-induced cramps and muscle weakness.

 

 

Congenital Myopathies

These myopathies present at birth with hyoptonia and abnormal muscle development.  Before advances in pathology techniques were made the congenital myopathies were called ‘Floppy Baby Syndrome’.  The main two conditions to know about are central core disease and nemaline rod myopathy.  Both cause delayed motor development, scoliosis, and long, thin face with a high arched palate.

 

Central core disease is associated with malignant hyperthermia when given inhaled anaesthetic agents.

 

 

MYOTONIC DISORDERS

Myotonia is the inability of a muscle to relax after stimulation.  It is often described as stiffness or cramping by patients.  The disorders are usually due to defects in ion channels.

 

Myotonic muscular dystrophy

Myotonic muscular dystrophy is an autosomal dominant condition with an unusual familial pattern: the gene mutation in question is a nucleotide triplet repeat so shows what is known as ‘genetic anticipation’, or worsening through the generations (see 'Genetics Counselling' article in Paediatrics).  The disease can range from slightly slow release of a clenched fist through to severe respiratory complications and death within the first year of life.  Infants are floppy and can have feeding and respiratory problems from birth.  Patients often have learning difficulties, cataracts, cardiomyopathy, testicular atrophy and dementia.

 

 

MANAGEMENT OF NEUROMUSCULAR DISORDERS

Neuromuscular disorders, as with many paediatric conditions, require a multidisciplinary team of epic proportions.

Management of Neuromuscular Disorders
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