Motor Neurone Disease

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.¹

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.² 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.

This is a degenerative condition that affects motor neurones, namely the anterior horn cells of the spinal cord and the motor cranial nuclei.³ 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 there are a small proportion of sufferers who have a familial form of the disease due to a mutation in the superoxide dismutase-1 gene.⁴ 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.^4,5

• MND is relatively uncommon with an annual incidence of about 2 cases per 100,000 population.^2,6 In those aged over 80, a more recent analysis of the Scottish register shows a standardised incidence of 10.2 per 100,000 in men and 6.1 per 100,000 in women.⁷
• Prevalence is about 5-7 per 100,000.²
• General practitioners can expect to see one or two cases in their career.
• US studies indicate a prevalence of about 5 cases per 100,000 population.^3,5

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 but this only accounts for about 5% of cases.

• 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 and lower motor neurone features (for example, with a wasted fasciculating biceps with a brisk, easily obtained biceps' reflex).
  • In three recognised patterns:
    • Limb onset - by far the commonest
    • Bulbar onset - 20% of cases
    • Respiratory onset - the least common
• The rarer variants of the disease can present in 2 ways:
  • With pure UMN features (primary lateral sclerosis).
  • With pure LMN features (progressive muscular atrophy).

Symptoms

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.
  But may occasionally cause problems in the leg or legs:
  • 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 late feature with significant speech difficulties).
  • Emotional lability (inappropriate laughing or crying) accompanies (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).²
• 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'.
  • Some patients with pseudo-bulbar 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.

Signs

• Lower motor neurone 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.

Diagnostic criteria

This is of course a diagnosis which needs a great deal of careful consideration given the poor prognosis. 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.
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):⁸

• Presence of:
  • Evidence of LMN degeneration by clinical, electrophysiological or neuropathologic 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 differential diagnosis is vast, dependent on the mode of presentation, clinical findings and co-morbidities. Diagnoses of particular importance have been singled out in the box below with features which distinguish them from MND.

• Diabetic amyotrophy
• Guillain-Barré syndrome
• Post-polio syndrome
• Myasthenia gravis or Lambert-Eaton myaesthenic 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, e.g. due to carcinomatosis or vascular-collagen disease
• Lyme disease
• Spinal muscular atrophy (Kennedy's syndrome)
• Hereditary polyneuropathies, e.g. 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 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.
• CT and/or MRI of the brain and spinal cord are useful in excluding other pathologies with similar presentations.
• 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 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:²

• 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 record Breaking Bad News.
• Impart information honestly, but without destroying hope.
• Maintain a positive emphasis on what can be done to help.

Non-drug

MND is an incurable condition that usually, though 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 general practitioners, 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.
• 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 (with10% weight lost or body mass index below 18.5).²
• 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 greatly to improve quality of life and survival.² 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 during the day, using a small nasal mask.
  

  The greatest advance in treating MND has been the discovery of the beneficial effects of non-invasive ventilation, in which the patient uses a mask ventilator system (usually bilateral positive airway pressure) overnight during sleep.2

• 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.

Drug treatments

• 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.^9,2 It may have a more significant effect on prolonging tracheostomy-free survival.¹⁰ It appears to be well-tolerated and of greater benefit the earlier it is started in the course of the disease.¹¹ 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.¹²
• 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.¹³
• 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 due to spasticity will usually respond to the use of the anti-spasmodic agents listed above, but NSAIDs 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.
• Advanced 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
• Constipation
• Spasticity and cramping of muscles
• Depression
• 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. 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.²
• About 30% of patients survive beyond 5 years.⁵ 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.