Synonyms: amyotrophic lateral sclerosis (ALS), Lou Gehrig's disease (USA form - named for a famous baseball player who succumbed to the disease), Charcot's disease, Charcot's syndrome, Charcot's sclerosis
Motor neurone disease (MND) is a rare but devastating illness which leads to progressive paralysis and eventual death. Although rare, many patients are both aware and fearful of it. It is therefore important in primary care to understand the presentation and to be able confidently to reassure worried patients who are unlikely to have a diagnosis of MND. A review of life-prolonging interventions, symptom-control and disease mechanisms is appropriate for non-specialists and outlined in this article.
Most cases of MND are due to ALS. However, other forms occasionally occur. These include:
- Progressive bulbar palsy - about 2 in 10 people with MND have this type. The muscles first affected are those used for talking, chewing and swallowing. See separate article Bulbar and Pseudobulbar Palsy for more details.
- Progressive muscular atrophy - this is an uncommon form of MND. The small muscles of the hands and feet are usually first affected, but muscle spasticity is absent.
- Primary lateral sclerosis - this is another rare type of MND. It mainly causes weakness in the leg muscles. Some patients with this type may also develop clumsiness in the hands or develop speech problems.
This is a degenerative condition that affects motor neurons, namely the anterior horn cells of the spinal cord and the motor cranial nuclei. It causes lower motor neurone (LMN) and upper motor neurone (UMN) dysfunction, leading to a mixed UMN/LMN picture of muscular paralysis, usually with LMN signs predominating. The cause of the disease is unknown, although 5% of those affected have a familial form of the disease due to a mutation in the superoxide dismutase-1 gene.[2, 3]
Current aetiological hypotheses focus on an abnormality of mitochondrial function causing oxidative stress in motor neurons. There may be several causes for such oxidative damage to motor neurons and the disease may just represent an end-stage phenotypic expression of these abnormalities.
- MND is relatively uncommon with an annual incidence of about 2 cases per 100,000 population. Prevalence is about 5-7 per 100,000. General practitioners can expect to see one or two cases in their career.
- It can occur at any age but is more common in people aged over 50. The male to female ratio is 2:1.
- About 5-10% of cases are inherited.
- The mean age of onset is 43-52 years in familial and 58-63 years in sporadic cases of ALS.
- Male sex, increasing age and hereditary disposition are the main risk factors.
MND is mostly a sporadic disease of middle and elderly life presenting in the sixth and seventh decades. However, it can present in younger patients, usually with familial MND.
- The classic form of the disease is also called amyotrophic lateral sclerosis (ALS). It tends to be focal in onset, with a particular group of muscles affected first. This presents In three recognised patterns:
- Limb onset - by far the most common.
- Bulbar onset - 20% of cases.
- Respiratory onset - the least common.
- Presents with symptoms and signs of degeneration of the upper and lower motor neurons, leading to progressive weakness of the bulbar, limb, thoracic and abdominal muscles.
- Other brain functions, including oculomotor and sphincter function, are relatively spared, but may be involved in some patients.
- Cognitive dysfunction may occur and 5-15% of patients develop dementia, usually of frontotemporal type.
- The rarer variants of the disease can present in two ways:
- With pure UMN features (primary lateral sclerosis).
- With pure LMN features (progressive muscular atrophy).
Patients or their families often notice problems occurring in one or more of the patterns below:
- Limb weakness - usually affects the upper limbs:
- Causes patients to drop objects or have difficulty manipulating objects with one hand (turning keys, writing and opening bottles).
- Wrist drop, stiffness, weakness or cramping of the hands may also occur.
- Patients may also notice a change in the appearance of their hands (due to wasting of the intrinsic muscles).
- Fasciculations of the muscles of the limbs may be noticed prior to weakness developing.
- Foot drop (early).
- Gait disorder.
- A sensation of heaviness of one or both legs.
- A tendency to trip.
- Difficulty in rising from low chairs and climbing stairs.
- Excessive fatigue when walking.
- Bulbar onset:
- The first sign is usually slurring of the speech (impaired tongue movement).
- Wasting and fasciculation of the tongue.
- Dysphagia (usually a late feature with significant speech difficulties).
- Accompanying emotional lability (inappropriate laughing or crying) - as with pseudobulbar palsies.
- Other symptoms are difficulty eating, drooling, dysarthria, dysphonia, choking events with meals, nasal regurgitation of fluids or pulmonary aspiration.
- Respiratory onset can present with:
- Dyspnoea and orthopnoea.
- Clinical features resulting from hypoventilation overnight (for example, waking, unrefreshing sleep, hypersomnolence and early morning headaches).
- Rarer features:
- Pain or sensory disturbance is not unknown but is not a common feature of the disease; it is usually the absence of pain or sensory disturbance that helps to distinguish MND from radiculopathies (nerve root pathology) that can cause a similar presentation in peripheral limbs.
- Symptoms due to impaired respiratory muscle function usually occur late in the disease but can occasionally be a presenting feature, causing 'air hunger'. Acute respiratory failure has been reported.
- Some patients with pseudobulbar palsy may have 'emotional incontinence', an over-reaction to sad or funny events that they are aware of as being abnormal.
- Cognitive impairment is not a normal feature but can affect some patients with bulbar palsy.
- LMD dysfunction in the limbs manifests as weakness, atrophy, fasciculations and hyporeflexia. The thighs are often a site of marked fasciculation. Fasciculation can be difficult to distinguish from arterial pulsation, so consider if there is an underlying arterial course before defining twitching movements as fasciculation.
- UMN dysfunction manifests as weakness predominating in the arm extensors and leg flexors with evidence of hypertonia, hyper-reflexia and upgoing plantar responses; the bulbar muscles may also show spasticity with an exaggerated jaw jerk.
- Ocular, sensory or autonomic dysregulation signs are usually late features of the disease.
- Asymmetrical distal weakness frequently occurs.
- Brisk reflexes will occur in a wasted limb.
- There is an absence of major sensory symptoms and pain.
- There is a relentless progression of symptoms and signs.
This is of course a diagnosis which needs a great deal of careful consideration given the poor prognosis. Nevertheless, it is equally important to ensure that the diagnosis is not unduly delayed. One study found that the average time from suspected diagnosis to confirmation was one year. The authors called for greater educational input in primary and secondary care and a fast-track referral service.
Diagnosis should be made after consideration of the clinical signs and symptoms together with investigations to exclude other causes. Important diagnoses which may cause confusion are listed in the box under 'Differential diagnosis', below.
Because of the very variable clinical presentation, the diagnostic criteria below have been devised, taking into account investigations to confirm the diagnosis and refute other possible causes (revised El Escorial Criteria):
- Presence of:
- Evidence of LMN degeneration by clinical, electrophysiological or neuropathological examination.
- Evidence of UMN degeneration by clinical examination.
- Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination.
- Together with the absence of:
- Electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration.
- Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.
The World Federation of Neurology (WFN) has proposed further revision in the light of advances in neurophysiological techniques which can accurately detect degenerative neurological changes. They recommend upgrading the neurophysiological findings and making them as significant as the clinical findings in the diagnosis of ALS.
The differential diagnosis is vast, dependent on the mode of presentation, clinical findings and comorbidities. Diagnoses of particular importance have been singled out in the box below with features which distinguish them from MND.
- Benign cramp fasciculation syndrome:
- Fasciculation or cramps usually affecting large muscles (for example, calves).
- The fasciculation is more common after exercise or with lack of sleep.
- There is no wasting or weakness on examination.
- There is no progression over time.
- Cervical radiculomyelopathy (multilevel degenerative disease of the cervical spine):
- This can present with a mixture of LMN wasting and weakness and UMN brisk reflexes and spasticity signs.
- There is pain (localised to the neck or radicular) and sensory disturbance.
- There are no bulbar symptoms and signs.
- The absence of UMN signs above the LMN signs increases the possibility of this diagnosis.
- MRI scan of the cervical spine can confirm the diagnosis.
- Dual pathologies:
- A cervical myelopathy and a co-existent peripheral neuropathy can present as a mixed upper-lower motor neurone picture.
- Sensory signs and symptoms and absence of bulbar symptoms help to diagnose this.
- Neurophysiological assessment and imaging will confirm the diagnosis.
- Multifocal motor neuropathy with conduction block:
- Often presents in young or middle-aged men as unilateral distal upper limb weakness with little evidence of wasting initially.
- This is an important rare diagnosis to consider in differential diagnosis of MND.
- In the correct clinical context, it can be diagnosed or excluded only by careful neurophysiological evaluation looking for conduction block.
- It is treatable and has a markedly different prognosis than that for MND.
- Inclusion body myositis:
- An inflammatory myopathy which presents with distal weakness without sensory symptoms.
- Clinically long finger flexors are affected preferentially (unusual in MND).
- Electromyography (EMG) and occasionally muscle biopsy are needed to confirm the diagnosis.
- Inclusion body myositis has a more benign prognosis than MND.
The list below shows further conditions that may have similar clinical features:
- Diabetic amyotrophy.
- Guillain-Barré syndrome.
- Post-polio syndrome.
- Myasthenia gravis or Lambert-Eaton myasthenic syndrome.
- Peripheral nerve lesions, particularly due to diabetic neuropathy.
- Thyrotoxicosis with associated myopathy.
- Spinal cord tumours.
- Cerebrovascular disease and stroke.
- Polymyositis or dermatomyositis.
- Glioma of brainstem.
- HIV-associated neuropathy/myopathy/radiculopathy (as one of the complications of HIV).
- Lepto-meningeal disease - eg, due to carcinomatosis or vascular collagen disease.
- Lyme disease.
- Spinal muscular atrophy (Kennedy's syndrome).
- Hereditary polyneuropathies - eg, Charcot-Marie-Tooth syndrome.
- Focal muscular atrophies (monomelic amyotrophy).
- Post-radiation myeloplexopathy.
- Viral plexopathies.
- Tay-Sachs disease (adult form).
There are no specific investigations that will confirm a diagnosis of MND. A range of investigations is carried out to confirm consistent features and exclude other possible pathologies, usually under the direction of a neurologist. It may take several months to decide that the clinical presentation, progression and investigation findings are consistent with the diagnosis. This cautious approach is understandable, given the prognosis of the illness and the devastation that being given the diagnosis may cause to a person's life. The investigations below may be conducted during the course of making the diagnosis:
- Electrophysiological studies such as EMG and nerve-conduction studies (NCS) will show a characteristic pattern but require careful interpretation, along with a consideration of the clinical features. In MND, EMG shows fibrillation and fasciculations. The motor units are polyphasic and have high amplitude and long duration. NCS should show normal motor and sensory conduction in MND. More sophisticated techniques have prompted recommendations (Awaji-shima consensus recommendations for the application of electrophysiological tests, as applied to the revised El Escorial Criteria) that the electrophysiological findings should be given equal weight to the clinical findings in the diagnosis of the condition.
- CT and/or MRI scanning of the brain and spinal cord are useful in excluding other pathologies with similar presentations. Neuro-imaging is not yet considered to be sufficiently sensitive to assess responses to treatment but the European Federation of Neurological Societies recommends that it should be incorporated into the evaluation of research trials.
- Blood tests to exclude other conditions, such as vitamin B12 and folate levels, HIV serology, Lyme disease serology, creatine kinase assay, serum protein electrophoresis, anti-GM1 antibodies (multifocal motor neuropathy with conduction block), urinary hexosaminidase-A assay (Tay-Sachs) and a host of other more specialised tests for rare conditions.
- Muscle biopsy may be considered to exclude or to diagnose myopathic conditions.
Giving the diagnosis
Part of the management of MND is giving the diagnosis and explaining the condition in an appropriately sensitive and informative way. The following points have been made:
- This is a difficult task and time; experience and expertise are needed.
- Follow the well-established good practice principles of breaking bad news.
- Impart information honestly but without destroying hope.
- Maintain a positive emphasis on what can be done to help.
Although specialists lead the diagnostic and monitoring process, GPs have a large part to play in the day-to-day management of the symptoms arising from the condition and the side-effects of medication.
MND is an incurable condition that usually, although not always, leads to death within a few years, with a period of distressing disability preceding it. Thus, the mainstay of management is in supporting the patient, their family and carers through this process and in delivering palliative care at the appropriate juncture. The following measures are helpful in prolonging the survival of those with MND and in helping them to maintain a sense of health, well-being and control over their lives:
- A multidisciplinary approach involving GPs, primary care nurses, occupational therapists, physiotherapists, speech therapists, dieticians, respite care providers, home care workers, hospital physicians and neurologists, along with many others, is likely to best serve the patient, and effective communication between all the interested parties is essential.
- GPs are particularly well placed in ensuring that patients and their carers know where to get information about any social or financial support that may be required.
- Regular physical, occupational and speech therapy to maintain strength and utility of the affected motor functions and allow use of aids designed to overcome specific disability problems.
- Dietetic support to allow adequate hydration and nutrition whilst the patient is able to feed independently, or with the aid of carers.
- Insertion of a gastrostomy tube should be considered when the patient is no longer able to feed by mouth. Current practice is to offer the option of enteral feeding to patients, either through percutaneous endoscopic gastrostomy (PEG), percutaneous radiological insertion of gastrostomy, or nasogastric tube (with 10% weight lost or a body mass index below 18.5).
- Communication can be greatly enhanced by the use of picture-boards or more advanced IT-based solutions tailored to the individual patient's needs and disabilities.
- When respiratory function is impaired, physiotherapy helps to clear pulmonary secretions and maintain respiratory health.
- Positive pressure ventilation may be used in patients who are no longer able to maintain adequate ventilation. This has been shown to improve quality of life and survival greatly. The machines are small and portable and various face masks are available . Patients quickly get used to wearing the masks overnight. In later stages some patients may use non-invasive ventilation (NIV) during the day, using a small nasal mask.
The greatest advance in treating MND has been the discovery of the beneficial effects of NIV, in which the patient uses a mask ventilator system (usually bilateral positive airway pressure) overnight during sleep.National Institute for Health and Care Excellence (NICE) guidelines recommend:
- Discussion about NIV at the time of diagnosis and at appropriate opportunities thereafter.
- The patient should be assessed for the symptoms and signs of respiratory impairment at three-monthly intervals.
- Patients who meet the NICE criteria for treatment of their respiratory impairment should be offered NIV. However, if the patient suffers from severe bulbar impairment or severe cognitive problems related to their respiratory impairment, NIV should only be offered if the patient has sleep-related symptoms or hypoventilation.
- If commenced, acclimatisation should occur during the day.
- Regular treatment should be given at night, before and during sleep.
- Hours of use should be built up as necessary.
- In patients with cognitive impairment, issues of capacity and consent may need to be considered.
- Riluzole (a neuroprotective glutamate-release inhibitor) is the only drug of proven disease-modifying efficacy.
- Its effects are modest, probably only prolonging lifespan by between two and four months.
- It may have a more significant effect on prolonging tracheostomy-free survival.
- It appears to be well tolerated and of greater benefit the earlier it is started in the course of the disease.
- It has been shown to act by blocking muscle acetylcholine receptors.
- It was hoped that antioxidants might prove beneficial. However, a recent Cochrane review concluded that the use of antioxidants was not supported by currently available clinical trial data.
- Other medications may be used to treat symptoms of the disease; for example:
- Drooling may be reduced by the use of anticholinergics such as hyoscine.
- Muscle cramps and spasticity can be treated with agents such as diazepam, baclofen, tizanidine, phenytoin and quinine.
- Respiratory distress and the sensation of choking may respond to opioid medications but this must be balanced against their tendency to cause respiratory suppression; they are very useful to treat this symptom in the palliative phase.
- Depression associated with MND may respond to the use of antidepressant medications.
- Pain often goes under-recognised and undertreated. It is thought to be due to spasticity but other mechanisms may be operant. The antispasmodic agents listed above are usually helpful but non-steroidal anti-inflammatory drugs and opioids, such as oral morphine, subcutaneous diamorphine and fentanyl patches, are also utilised, particularly in the palliative phase.
End of life care
Inevitably, the disease will progress and both patients and carers may wish to discuss the terminal phase of the illness. Careful discussion about this at a pace determined by the patient, family and carers helps to shape what form care will take. Issues which frequently come up include:
- Hospice care - this may be useful in the later stages of the disease for respite.
- Advance directives - information on these can be given and this can help implementation of patients' wishes.
- Management of symptoms - for example:
- Respiratory distress - this can be treated with opiates.
- Choking - lorazepam sublingually can quickly relieve choking episodes.
- Dyspnoea - if severe and prolonged, is an indication for subcutaneous morphine.
- Respiratory failure and death.
- Pneumonia due to infection or aspiration.
- Urinary tract infections.
- Spasticity and cramping of muscles.
- Loss of speech as a means of communication.
- Immobility and attendant disability.
- Complications of immobility such as skin infections/bedsores and ulcers.
- Cognitive deterioration is rare but is seen occasionally.
- MND is usually a rapidly progressive and fatal disease but the rate of progression is variable.
- Median survival is two to four years.
- End of life care with all that this implies needs a co-ordinated sensitive approach. More than 90% of patients die in their sleep, as a result of increasing hypercapnia (respiratory failure with or without pneumonia) and choking to death is not seen in clinical practice.
- There appears to be a small subgroup of patients (5-10%) surviving for a decade or more.
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