17.3 Neuromuscular disorders
Neuromuscular disorders of childhood have become a focus of increasing attention in recent years. Although many of these conditions are difficult to diagnose without sophisticated investigations, and they are generally incurable, this group of disorders cannot be ignored because of the significant morbidity and mortality associated with them, their genetic implications and the arrival of potential therapies. Early diagnosis is important in the rational management of these disorders as it allows provision of accurate prognostic and genetic information. Accurate diagnosis in this wide array of disorders is dependent on a careful clinical assessment followed by confirmatory and appropriate investigations. Recent advances have unravelled the molecular biology of many neuromuscular conditions, but the clinical assessment of patients remains the cornerstone of diagnosis and management.
The management of neuromuscular disorders requires recognition, diagnosis, therapy and counselling.
Recognition that a child’s presenting symptoms or signs may be due to peripheral neuromuscular disease
Please listen to the patient; he’s trying to tell you what disease he has.
(Michael H. Brooke 1977 A Clinician’s View of Neuromuscular Disease. Williams and Wilkins: Baltimore)
Although the hallmark of neuromuscular disorders is weakness, parents do not come into the consulting room saying, ‘I’m worried because my child is weak’. The physician needs to recognize that the presenting symptoms or signs relate to the neuromuscular system before the diagnostic process begins. Failure of this recognition results in diagnostic delay. Although this failure may not affect the ultimate prognosis, it adds considerably to patient and parental frustration. A tragedy occurs when opportunities for prevention are missed and a second affected child is born to the immediate or extended family.
Common presenting complaints of neuromuscular disorders include:
Another trap in the recognition of neuromuscular disease in childhood is that classical neurological signs, readily demonstrated at the end of a disease process in adult patients, are often absent in children at the beginning of the disease process. For example, adults with Charcot–Marie–Tooth disease very often have pes cavus, distal muscle wasting and generalized areflexia. In children, Charcot–Marie–Tooth disease presents with an abnormal walk or run, clumsiness and frequent falls. Foot deformity is a presenting symptom in a minority. In addition, although areflexia is the rule in adult patients, about 10% of children with Charcot–Marie–Tooth disease have normal reflexes at presentation. Not understanding the age-dependent symptoms and signs of neuromuscular disorders will lead to failure to recognize them in childhood.
Other modes of presentation include a family history of neuromuscular disease; weakness, hypotonia, respiratory or feeding difficulty in the neonatal period; delayed motor milestones; abnormal gait (particularly toe-walking); and orthopaedic abnormalities such as foot deformity or scoliosis. Some patients present with non-neuromuscular problems, such as intellectual disability or delayed language development, for example in Duchenne muscular dystrophy.
Diagnosis of neuromuscular disease based on anatomical, electrophysiological, biochemical, histopathological or DNA identification
After recognizing that the symptoms are due to neuromuscular disease, the differential diagnosis is based on a logical anatomical approach. Although this may appear overly simplistic, as some disorders may affect more than one anatomical area or be multisystemic, this approach will provide a broad differential diagnosis that leads on to definitive diagnosis.
The anatomical localization is based on the clinical findings listed in Table 17.3.1 and includes disorders affecting the:
The use of a timeframe of symptoms, such as acute, subacute or chronic, will also provide an important frame for the differential diagnosis.
The definitive diagnosis rests on a combination of:
• clinical history and examination
• serum muscle enzymes, particularly creatine kinase (CK)
• electrophysiology (e.g. nerve conduction studies, electromyography, repetitive nerve stimulation)
• histology of muscle and/or nerve
• metabolic studies (e.g. muscle glycogen, carnitine assay, mitochondrial studies)
Anterior horn cell disorders
Acute
Poliomyelitis
This disorder is rare in developed countries, but should still be considered where there is acute onset of weakness of a single limb, or with patchy asymmetrical distribution, particularly if this is associated with fever, vomiting, neck or back stiffness, and muscle pain or spasms. Sensory abnormalities are absent.
Chronic
In childhood the chronic disorders characterized pathologically by degeneration of anterior horn cells and associated clinically with progressive muscle weakness are called the spinal muscular atrophies (SMAs). The important SMA syndromes and their classification are listed in Table 17.3.2.
Spinal muscular atrophy type I (Werdnig–Hoffmann disease)
This autosomal recessive disorder occurs in approximately 1 in 6000 live births, making it the most common fatal autosomal recessive disorder of early childhood. The earliest symptom may be decreased fetal movements in late pregnancy. Presentation is invariably before 6 months of age and is either at birth with hypotonia, weakness, joint deformity and respiratory difficulty, or more commonly later with marked hypotonia and limb weakness, poor feeding, poor cough and cry. The onset is sometimes relatively rapid and when first seen the child is usually severely weak (Fig. 17.3.1). Weakness, although generalized, is maximal proximally in the shoulder and hip girdle muscles. Intercostal muscle weakness leads to chest deformity, a poor cough and a weak cry. The respiratory pattern becomes diaphragmatic. Deep tendon reflexes are absent. Fasciculations of the tongue are an important clinical clue, but this can be a difficult sign to be certain about and one can only be confident if the baby is relaxed and there are no ‘voluntary’ movements of the tongue. Facial weakness in SMA is very mild and the extraocular movements remain full, giving the baby an alert appearance. Death, usually from pneumonia and respiratory failure, occurs by 18 months of age in 95% of patients, with those with onset in the first 2 months of life having the shortest survival.
Practical points• Tongue fasciculations can be seen with certainty only when the tongue has no voluntary movement, i.e. is at rest in the floor of the mouth and the child is not crying or actively moving the tongue.
• The presence of deep tendon reflexes makes it extremely unlikely that the child has type 1 SMA and an alternative diagnosis should be considered.
SMA is caused by homozygous deletions of the SMN1 gene, causing loss of SMN protein production in motor neurons of the anterior horn of the spinal cord. Prenatal diagnosis and carrier testing of relatives are available.
Various therapeutic strategies are being trialled. Most are designed to upregulate SMN protein expression via a variety of mechanisms.
Spinal muscular atrophy type 2
The genetic abnormality in SMA types 2 and 3 is allelic to that of SMA type 1, but these are milder forms of the disease. The clinical onset of SMA type 2 is almost invariably before 3 years of age, with hypotonia, weakness and delayed motor milestones. The clinical picture is one of severe generalized weakness and wasting, with proximal predominance. Deep tendon reflexes are decreased or absent and often there are fasciculations of the tongue. The facial muscles may be mildly weak but eye movements remain normal and the patient is usually normal intellectually. Many patients have a fine, rapid tremor of the hands. Children with SMA type 2 never walk unsupported. Survival varies from 18 months through to adult life. Major management problems include the prevention of orthopaedic deformity, especially scoliosis, and the management of the respiratory complications of muscle weakness. Prompt treatment of chest infections prolongs survival, and many children and adults with SMA type 2 benefit from nocturnal non-invasive ventilatory support. Patients with a later onset and a moderately benign clinical course are classified as SMA type 3 (Kugelberg–Welander syndrome). Most have onset in the first two decades, with only a few in the third decade, and survival is usually for many decades. Persons with SMA type 3 are able to walk at some point, and many remain ambulant into adulthood.
Peripheral nerve disorders
A number of peripheral neuropathies with various time courses (acute, subacute or chronic) occur in childhood. They may be inherited or acquired; they may involve motor, sensory or autonomic fibres, or commonly a mixture of all three. Pathologically, they may be associated with combinations of demyelination and axonal degeneration. Some central nervous system degenerative disorders, such as Krabbe disease and metachromatic leukodystrophy, also affect the peripheral nerves. The most common nerve disorders of childhood are Guillain–Barré syndrome (GBS) and Charcot–Marie–Tooth disease (CMT). Chronic inflammatory demyelinating polyneuropathy (CIDP), while uncommon, is important because it is responsive to immunotherapies.
Acute neuropathies
Guillain–Barré syndrome
GBS is the most common acute neuropathy in clinical practice and can occur at any age, although it is rare in infancy. An infection, commonly of the upper respiratory tract or gastrointestinal tract (Campylobacter jejuni), precedes the neurological syndrome in at least 50% of cases. Typical GBS is a monophasic illness with symmetrical, ascending weakness involving proximal and distal muscles. Paraesthesia and muscle pain may be presenting complaints but sensory impairment is usually minimal. Severe back pain and stiffness may occur, especially in young children. The deep tendon reflexes are lost early in the course of the illness. Cranial nerve involvement, particularly of the facial nerve, is relatively common. Autonomic involvement can cause wide fluctuations of the blood pressure as well as cardiac arrhythmias and bladder dysfunction. Respiratory failure occurs in about 30% of patients. GBS typically progresses over less than 4 weeks, with most patients reaching their maximal deficit within 2 weeks of onset. Artificial ventilation is occasionally required. Recovery continues over weeks to months, with most children returning to normal function. Some more severely affected children have residual weakness, most commonly of ankle dorsiflexion. Fatigue is common during the recovery period.
Diagnosis is based on the clinical features, with increased cerebrospinal fluid (CSF) protein with only a few, if any, cells in the CSF. Spinal magnetic resonance imaging (MRI) and/or nerve conduction studies are useful in difficult diagnostic situations. All children with suspected GBS should be admitted to hospital for monitoring of their respiratory status, blood pressure and cardiac rhythm. Management of GBS requires special expertise in medical and nursing care, and affected children should be referred to centres used to dealing with this condition. Supportive therapy is very important. Intravenous gammaglobulin or plasmapheresis, if used early, may hasten recovery, but is not always required for milder cases.
Chronic neuropathies
Chronic inflammatory demyelinating peripheral neuropathy (CIDP)
This rare but treatable autoimmune neuropathy presents subacutely or as a chronic neuropathy. The course can be monophasic but is more commonly relapsing/remitting. Acute presentations can occur and may cause confusion with GBS. Symptoms and signs of weakness, often most prominent proximally, bring the child to medical attention. The diagnosis is confirmed by nerve conduction studies, increased CSF protein and, if there is diagnostic doubt, pathological abnormalities on nerve biopsy. CIDP is treated with intravenous immunoglobulin, corticosteroids and other immunosuppressive agents.
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