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 neurones, 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 sufferers who have a familial form of the disease due to a mutation in the superoxide dismutase-1 gene. Current aetiological hypotheses focus on an abnormality of mitochondrial function causing oxidative stress in motor neurones. There may be several causes for such oxidative damage to motor neurones and the disease may just represent an end-stage phenotypic expression of these abnormalities.
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- Motor neurone disease (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.
Motor neurone disease (MND) is mostly a sporadic disease of middle and elderly life presenting in the sixth and seventh decades. However, it can present in much 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:
- With a mixture of upper motor neurone (UMN) and lower motor neurone (LMN) features (for example, with a wasted fasciculating biceps with a brisk, easily obtained biceps' reflex).
- In three recognised patterns:
- Limb onset - by far the most common.
- Bulbar onset - 20% of cases.
- Respiratory onset - the least common.
- 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:
- 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 motor neurone disease (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 lower motor neurone (LMN - wasting and weakness) and upper motor neurone (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 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 motor neurone disease (MND). A range of investigations are 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 motor neurone disease (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 bad news breaking: see separate article 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 MND sufferers 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 Clinical 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 suffers from 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 but its effects are modest, probably only prolonging lifespan by between 2 and 4 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 is the subject of guidance issued by NICE; its use should be initiated and supervised by a neurologist who is experienced in the management of MND, with the assistance of primary care practitioners, according to an agreed protocol.
- 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.
- Motor neurone disease (MND) is usually a rapidly progressive and fatal disease. Median survival is 3-5 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.
- About 30% of patients survive beyond five years. There appears to be a small subgroup of patients (up to 10-20% in some series) who have an early onset of the disease and who survive in the long term due to slow progression of the illness; they tend to be male and have a limb, rather than bulbar, onset of the disease.
Further reading & references
- Motor Neurone Disease Association
- International Alliance of ALS/MND Associations
- Roche JC, Rojas-Garcia R, Scott KM, et al; A proposed staging system for amyotrophic lateral sclerosis. Brain. 2012 Mar;135(Pt 3):847-52. Epub 2012 Jan 23.
- Murphy P, Lyall R, Hart N, et al; Assessment of respiratory muscle strength in motor neurone disease: is asking Eur Respir J. 2010 Feb;35(2):245-6.
- De Vito EL, Suarez AA, Monteiro SG; The use of full-setting non-invasive ventilation in the home care of people with J Med Case Reports. 2012 Jan 30;6(1):42.
- Charcot's Disease; Charcot's Disease (details of Charcot's discovery of MND and the many other eponymous conditions that bear his name), whonamedit.com
- McDermott CJ, Shaw PJ; Diagnosis and management of motor neurone disease. BMJ. 2008 Mar 22;336(7645):658-62.
- Armon C, Amyotrophic Lateral Sclerosis (ALS), Medscape, Aug 2011
- Wood-Allum CA, Barber SC, Kirby J, et al; Impairment of mitochondrial anti-oxidant defence in SOD1-related motor neuron injury and amelioration by ebselen. Brain. 2006 Jul;129(Pt 7):1693-709. Epub 2006 May 15.
- Orrell RW; GPs have key role in managing motor neurone disease. Practitioner. 2011 Sep;255(1743):19-22, 2.
- Breuer ME, Willems PH, Russel FG, et al; Modeling mitochondrial dysfunctions in the brain: from mice to men. J Inherit Metab Dis. 2012 Mar;35(2):193-210. Epub 2011 Jul 14.
- Lad TS; An 'acute' presentation of motor neuron disease. Acute Med. 2011;10(3):140-1.
- Mitchell JD, Callagher P, Gardham J, et al; Timelines in the diagnostic evaluation of people with suspected amyotrophic Amyotroph Lateral Scler. 2010 Dec;11(6):537-41. Epub 2010 Jun 22.
- Inghilleri M, Iacovelli E; Clinical neurophysiology in ALS. Arch Ital Biol. 2011 Mar;149(1):57-63. doi: 10.4449/aib.v149i1.1264.
- Okita T, Nodera H, Shibuta Y, et al; Can Awaji ALS criteria provide earlier diagnosis than the revised El Escorial J Neurol Sci. 2011 Mar 15;302(1-2):29-32. Epub 2011 Jan 6.
- Guidelines on the use of neuroimaging in the management of motor neuron diseases, European Federation of Neurological Societies (2010)
- Lee CN; Reviewing evidences on the management of patients with motor neuron disease. Hong Kong Med J. 2012 Feb;18(1):48-55.
- Zoing M, Kiernan M; Motor neurone disease - caring for the patient in general practice. Aust Fam Physician. 2011 Dec;40(12):962-6.
- O'Brien MR, Whitehead B, Murphy PN, et al; O'Brien MR, Whitehead B, Murphy PN, et al; Social services homecare for people with motor neurone disease/amyotrophic Palliat Med. 2012 Mar;26(2):123-31. Epub 2011 Mar 7.
- Motor neurone disease - non-invasive ventilation, NICE Clinical Guideline (July 2010)
- Miller RG, Mitchell JD, Lyon M, et al; Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Sep;4(3):191-206.
- Miller RG, Mitchell JD, Moore DH; Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;3:CD001447.
- Zoccolella S, Beghi E, Palagano G, et al; Riluzole and amyotrophic lateral sclerosis survival: a population-based study in Eur J Neurol. 2007 Mar;14(3):262-8.
- Deflorio C, Palma E, Conti L, et al; RILUZOLE BLOCKS HUMAN MUSCLE ACETYLCHOLINE RECEPTORS. J Physiol. 2012 Mar 19.
- Motor neurone disease, NICE (2001)
- Orrell RW, Lane RJ, Ross M; A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Amyotroph Lateral Scler. 2008 Aug;9(4):195-211.
- Saliva Control, Motor Neurone Disease Association, 2010
- Chio A, Canosa A, Gallo S, et al; Pain in amyotrophic lateral sclerosis: a population-based controlled study. Eur J Neurol. 2012 Apr;19(4):551-5. doi: 10.1111/j.1468-1331.2011.03540.x. Epub
- Malnutrition in ALS, ALS Association, 2010
- Clem K et al, Emergent Treatment of Amyotrophic Lateral Sclerosis (ALS), Medscape, May 2011
|Original Author: Dr Sean Kavanagh||Current Version: Dr Laurence Knott||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 16/05/2012||Document ID: 2469 Version: 25||© EMIS|
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