Motor neurone disease - part one

THE ESSENTIALS 

- A large group practice will see one case of ALS every two or three years.

- Most patients present with muscle weakness, fasciculations and cramps.

- Suspicion of the diagnosis warrants urgent outpatient referral.

- Diagnosis is largely clinical, supported by laboratory tests.

- Intense research is carried out into why motor neurones die in ALS.

1. BASIC FACTS AND FIGURES

Motor neurone disease (MND) is one of the three most common neurodegenerative diseases with onset in adulthood, along with Alzheimer's disease and Parkinson's disease.

There are a number of forms of MND, of which the most common is amyotrophic lateral sclerosis (ALS). ALS is characterised by both upper and lower motor neurone symptoms and signs in limb, trunk and bulbar muscles.

Other forms of MND include progressive muscular atrophy, progressive bulbar palsy and primary lateral sclerosis, a much less frequently seen form, which is a slowly progressive upper motor syndrome. There are also several ALS-plus syndromes. Patients with these conditions meet ALS criteria but have additional extrapyramidal signs, cerebellar signs or dementia.

This review will focus on ALS.

Amyotrophic lateral sclerosis ALS is distributed uniformly worldwide although there are geographical hotspots of the ALS-plus syndromes. The incidence of ALS is 1-2 per 100,000 of the population, with a prevalence of 4-6 per 100,000. In the UK there are approximately 5,000 people affected by ALS at any one time. This means that a GP practice with 10,000 patients is likely to see one case of ALS every two to three years.

Risk factors There are only three proven risk factors for ALS: increasing age, male sex and the inheritance of a predisposition to the disease. The average age of onset of ALS is about 55 years. Incidence is low until the age of 40 and then rises sharply to peak at about 65 years. There is a male predominance in MND with a male:female incidence ratio of 1.6:1. In 90 per cent of cases, ALS is sporadic, but in the remainder the disease is familial with an autosomal dominant mode of inheritance.

Previous physical trauma, electric shock, and a high level of athleticism or of occupational exertion have all been reported to be commoner in ALS patients, but these risk factors are controversial. Recent studies report unexplained excesses of ALS in Gulf War veterans and Italian professional footballers. No consistent dietary risk factors have been established.

In ALS, there is progressive dysfunction and death of lower motor neurones in the spinal cord and brainstem and upper motor neurones in the motor cortex. Affected individuals develop muscle weakness, wasting and fasciculations (lower motor symptoms and signs), accompanied by stiffness and pathologically brisk reflexes (upper motor symptoms and signs).

The disease affects bulbar, respiratory and limb muscles and is progressive.

Death is usually the result of respiratory failure caused by ventilatory muscle weakness and typically happens within three to five years of disease onset.

KEY POINTS

- Amyotrophic lateral sclerosis (ALS) is the commonest form of MND.

- The incidence of ALS is about 1-2 per 100,000.

- Risk factors for ALS are increasing age, male sex and the inheritance of a predisposition to the disease.

- About 10 per cent of ALS cases are familial.

2. WHAT MAKES MOTOR NEURONES DIE?

Motor neurones are post-mitotic cells so cannot regenerate by replication if damaged. It is still unclear what causes the selective dysfunction and death of motor neurones in ALS but there is now experimental evidence for several competing hypotheses. It is thought that the cumulative effects over time of a combination of oxidative stress, excitotoxicity due to excess glutamate, protein aggregation and mitochondrial injury may be responsible, coupled to characteristics inherent to motor neurones which make them particularly vulnerable.

Genetic factors In 1993, it was found that mutations of the gene encoding a free radical scavenging enzyme called copper/zinc superoxide dismutase (SOD1) could cause ALS. So far over 110 different SOD1 mutations have been described.

They underlie about 20 per cent of familial ALS and about 2 per cent of all cases.

It is clear that an additional toxic property of SOD1 conferred by the mutations causes motor neurone injury. It is less clear why motor neurones are selectively injured as the enzyme is found in all cells. The SOD1 transgenic mouse is a good model of human ALS and research in this model may help answer some of these questions. The search is on to discover the genes responsible for the remaining 80 per cent of familial ALS.

Excitotoxicity

Glutamate is the major excitatory neurotransmitter in the human central nervous system (CNS). Motor neurones are activated by the release of glutamate, which acts on surface receptors. Overstimulation of these receptors (excitotoxicity) may contribute to motor neurone injury in ALS.

Riluzole, a drug that reduces the pre-synaptic release of glutamate, is the only drug currently approved for use as a disease-slowing agent in ALS.

Oxidative stress Free radicals are generated as unwanted by-products of oxidative respiration by mitochondria and oxidative stress occurs when levels of free radicals overwhelm anti-oxidant defences. The finding that mutations to SOD1, a free radical scavenger, causes 20 per cent of familial ALS suggested that oxidative stress might be important in the pathogenesis of ALS. Evidence of oxidative damage to proteins, lipids and DNA has now been found in the CNS of patients with ALS.

KEY POINTS

- Motor neurones are post-mitotic therefore cannot regenerate when damaged.

- It is still unknown why motor neurones are selectively affected in ALS.

- Oxidative stress, excitotoxicity, protein aggregation and mitochondrial injury may all contribute.

- Mutations to superoxide dismutase 1 (SOD1) cause 20 per cent of familial ALS.

- The genes responsible for the remaining 80 per cent of familial ALS are unknown.

3. SYMPTOMS OF ALS

Most patients present initially with muscle weakness in the absence of sensory loss. It is unusual for patients to present with fasciculations alone.

Where upper motor neurone involvement is prominent, patients might complain of stiff limbs. The disease starts in the limbs in about 80 per cent of patients, and in the bulbar muscles in the remainder. Initial symptoms are often asymmetrical and might involve only one limb. Of patients presenting with predominantly bulbar symptoms, older women are over-represented.

Limb symptoms ALS presenting in the upper limb can first manifest as difficulty manipulating objects with the fingers of one hand, for example trouble turning a key or unscrewing bottle tops.

As muscle weakness progresses, patients might find it difficult to write and might complain of difficulty brushing their hair, a symptom of proximal weakness. Patients presenting with lower limb symptoms often complain of dragging one leg or a tendency to trip. Patients might notice difficulty climbing stairs or standing from a low chair, symptoms of proximal muscle weakness. Fatigue is also common.

Bulbar symptoms

Patients with early bulbar involvement in ALS present with or complain of indistinct speech, the slurring worsening when they are tired. Subtle vocal changes such as the development of a nasal overtone due to palatal weakness are often noticed first by family. Spasticity of the bulbar muscles makes speech effortful, with a tight, strangled quality. Lower motor weakness of the vocal cords can result in hoarseness.

Dysphagia usually develops only when dysarthria has become significant.

Patients take progressively longer than their partners to finish a meal.

Manipulating food inside the mouth becomes difficult because of tongue weakness and chewing becomes tiring. Patients gradually modify the texture of what they eat. Poor lip-seal can result in spillage and liquid can regurgitate into the nose due to nasopharyngeal incompetence. Weight loss occurs once these problems can no longer be compensated for.

Respiratory symptoms

In most patients respiratory symptoms are a late feature but, rarely, might be the presenting complaint. Early-morning headache, waking unrefreshed from sleep and sleepiness into the morning are all suggestive. Affected patients often sleep propped up. Loss of appetite might often be due to early respiratory compromise. Patients often develop a weak cough.

As respiratory muscle weakness progresses, patients become short of breath on exertion, on bending down or after a large meal, and eventually suffer from breathlessness at rest.

Other symptoms Bulbar weakness and poor co-ordination of swallowing can cause coughing spells. Reduced swallowing of saliva can cause drooling and patients might also suffer from emotional lability (pseudobulbar palsy), which causes them to laugh or cry inappropriately.

Although most ALS patients show no overt deterioration in intellect, neuropsychological testing can reveal subclinical deficits in frontal lobe functioning. Overt frontotemporal dementia accompanies motor signs in about 3-5 per cent of cases.

KEY POINTS

- ALS starts in the limbs in 80 per cent of patients.

- Bulbar involvement affects speech and the ability to swallow.

- Respiratory involvement is usually late but rarely might be the presenting problem

- Other seemingly less serious symptoms can affect quality of life significantly.

- Frontotemporal dementia accompanies 3-5 per cent of ALS cases.

4. CLINICAL SIGNS OF ALS

A combination of upper and lower motor neurone signs are found in a distribution extending beyond a single spinal root or peripheral nerve, and in the absence of sensory abnormalities. Patients might have only upper or lower motor neurone signs at the outset.

Early on, muscle weakness might have a characteristic distribution, with initial involvement of the thenar and interosseus muscles and wrist and finger extensors. More proximally, biceps, deltoid and infraspinatus are affected. The wrist and finger flexors and triceps are relatively spared.

In the lower limbs, weakness often first involves hip flexion and ankle dorsiflexion. Plantar flexion and the quadriceps muscles are often relatively spared. Paradoxical movement of the abdominal wall on breathing reflects diaphragmatic weakness.

Fasciculations are easiest to see in larger muscles such as the biceps, deltoid, triceps and quadriceps muscles and in the small muscles of the hands. Brisk limb reflexes or normal reflexes in the presence of significant muscle atrophy characterise upper motor neurone involvement. Plantar responses can be up-going. Neck extensor weakness is common and causes head-drop.

Bulbar signs Both upper and lower motor neurone signs might be found in patients with bulbar involvement. The tongue often shows fasciculations, wasting and weakness (lower motor signs), while spasticity causes slow tongue movements.

Tongue fasciculations are best looked for with the tongue relaxed inside an open mouth. A brisk jaw jerk implies upper motor bulbar involvement.

KEY POINTS

- ALS features upper and lower motor neurone weakness of limb and bulbar muscles.

- Lower motor neurone signs include muscle weakness, wasting and fasciculation.

- Upper motor neurone signs include muscle weakness, increased tone and brisk limb reflexes.

- A brisk jaw jerk and spastic dysarthria point to upper motor neurone bulbar involvement.

- Tongue wasting and fasciculation indicates lower motor neurone bulbar involvement.

5. ESTABLISHING THE DIAGNOSIS

The diagnosis of ALS is essentially clinical because there is no specific diagnostic test. Laboratory testing is used to exclude other disorders and to support the clinical diagnosis. The suspicion of ALS should prompt urgent referral to a neurologist.

The El Escorial criteria

The El Escorial criteria were designed to standardise the diagnosis of ALS for the recruitment of patients to clinical trials.

Four spinal cord regions are defined: brainstem, cervical, thoracic and lumbosacral. A clinically certain diagnosis is made by the demonstration of upper and lower motor neurone signs in at least three regions, plus evidence of progression. Because the El Escorial criteria are so stringent, many patients will have a working diagnosis of ALS long before they meet the criteria.

Neurophysiological testing

Neurophysiological assessment is used to support the clinical evidence of ALS and to exclude other causes of the patient's symptoms. Evidence on electromyography (EMG) of muscle denervation and reinnervation in at least two spinal cord regions - not corresponding to a single nerve root or peripheral nerve territory and without involvement of the sensory nerves - is strongly suggestive of ALS. EMG findings might be positive in spinal cord regions as yet clinically unaffected.

In some patients a MRI or CT might be necessary to exclude structural lesions of the brain or spinal cord. Muscle biopsy might be needed to exclude inflammatory myopathy. Most biochemical investigations are normal in ALS. Creatinine kinase can be two or three times the normal level in half of patients. CSF protein might be slightly elevated and 5 per cent of ALS patients have a serum paraprotein band.

Differential diagnosis

Differential diagnoses include benign cramp-fasciculation syndrome, radiculomyopathies caused by degenerative disease of the spine, myasthenia gravis, motor neuropathies, myo- pathies such as polymyositis, hyperthyroidism, hyperparathyroidism and lead poisoning.

KEY POINTS

- Seek early confirmation by a neurologist.

- Diagnosis of ALS is largely clinical and is formalised by the El Escorial criteria.

- Electromyography (EMG) can help confirm the diagnosis.

- Imaging and blood testing is done to exclude other diagnoses.

FURTHER RESOURCES

Further reading

Amyotrophic lateral sclerosis. Edited by R H Brown Jr, V Meninger, M Swash. Published by Taylor and Francis, 1999.

Palliative care in amyotrophic lateral sclerosis (motor neurone disease). Edited by D Oliver, G Domenico Borasio, and D Walsh. Oxford University Press, 2000.

Websites

See Medicine on the Web, page 43.

Previously in Clinical Review

Log on to GPonline.com to print an A4 copy of any Clinical Review published in the past year.

- Coeliac disease (17 March)

NEXT WEEK: Motor neurone disease - part two, by Dr Clare Wood-Allum.

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