Motor neurone disease

Motor neurone disease (MND) is a rare but devastating neurodegenerative condition that affects the brain and spinal cord, leading to progressive paralysis and eventual death¹ . Most cases of MND are due to amyotrophic lateral sclerosis (ALS). However, other forms occasionally occur. These include² :

• Progressive bulbar palsy - the muscles first affected are those used for talking, chewing and swallowing. See the separate Bulbar and Pseudobulbar Palsy article for more information.

• 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 a 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.

Pathophysiology

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 gene³ .

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 abnormalities⁴ .

Epidemiology

• The incidence is 2-4/100,000 per annum), with onset typically in the sixth and seventh decades⁵ .

• The male to female ratio is 2:1³ .

• About 5-10% of cases are inherited⁶ .

• Male sex, increasing age and hereditary disposition are the main risk factors⁷ .

Presentation³

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.

MND causes progressive muscular weakness that may first present as isolated and unexplained symptoms. These symptoms may include¹ :

• Functional effects of muscle weakness, such as loss of dexterity, falls or trips.

• Speech or swallowing problems, or tongue fasciculations (this is known as bulbar presentation).

• Muscle problems, such as weakness, wasting, twitching, cramps and stiffness.

• Breathing problems, such as shortness of breath on exertion or respiratory symptoms that are hard to explain.

• Effects of reduced respiratory function, such as excessive daytime sleepiness, fatigue, early morning headache or shortness of breath when lying down.

• MND may first present with cognitive features, which may include:

  • Behavioural changes.

  • Emotional lability (not related to dementia).

  • Frontotemporal dementia.

ALS 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.

ALS 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 type⁷

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).

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.

• However, occasionally problems in the leg or in both legs may occur:
  

  • 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 reported⁸ .

  • 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.

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.

• Upper motor neurone dysfunction manifests as weakness predominating in the arm extensors and leg flexors with evidence of hypertonia, hyperreflexia 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

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.

Differential diagnosis

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.

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).

Investigations⁹

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 condition¹⁰ .

• CT and/or MRI scanning 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 to diagnose myopathic conditions.

Management¹¹

If you suspect MND, refer the person without delay and specify the possible diagnosis in the referral letter. Contact the consultant neurologist directly if you think the person needs to be seen urgently¹ .

Giving the diagnosis

Follow the well-established good practice principles of breaking bad news.

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 medication¹² .

Non-drug

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 required¹³ .

• 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.

• Exercise programmes¹ :

  • Consider an exercise programme for people with MND to:
    

    • Maintain joint range of movement.

    • Prevent contractures.

    • Reduce stiffness and discomfort.

    • Optimise function and quality of life.

• If a person needs orthoses to help with muscle problems, they should be referred to orthotics services without delay, and the orthoses should be provided without delay¹ .

• 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.

Drug treatments

Riluzole (a neuroprotective glutamate-release inhibitor) is the only drug of proven disease-modifying efficacy¹⁴ :

Riluzole is recommended by NICE for the treatment of ALS. It should be initiated by a neurological specialist with expertise in the management of MND. Routine supervision of therapy should be managed by locally agreed shared care protocols undertaken by general practitioners¹⁵ .

A Cochrane review found that riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with ALS¹⁶ .

Symptomatic treatments

There is limited evidence of the effectiveness of symptomatic drug treatments¹⁷ . NICE recommends¹ :

• Muscle cramps: consider quinine as first-line treatment. If quinine is not effective, not tolerated or contra-indicated, consider baclofen instead as second-line treatment. If baclofen is not effective, not tolerated or contra-indicated, consider tizanidine, dantrolene or gabapentin.

• Muscle stiffness, spasticity or increased tone: consider baclofen, tizanidine, dantrolene or gabapentin to treat. If these treatments are not effective, not tolerated or contra-indicated, consider referral to a specialist service for the treatment of severe spasticity.

• Problems with saliva: assess the volume and viscosity of the saliva and the person's respiratory function, swallowing, diet, posture and oral care.

• Drooling of saliva (sialorrhoea): provide advice on swallowing, diet, posture, positioning, oral care and suctioning. Consider a trial of antimuscarinic medicine as the first-line treatment. Consider glycopyrrolate as the first-line treatment for sialorrhoea if there is cognitive impairment, because it has fewer central nervous system side-effects. If first-line treatment for sialorrhoea is not effective, not tolerated or contra-indicated, consider referral to a specialist service for botulinum toxin A.

• Thick, tenacious saliva:

  • Review all current medicines, especially any treatments for sialorrhoea.

  • Provide advice on swallowing, diet, posture, positioning, oral care, suctioning and hydration.

  • Consider treatment with humidification, nebulisers and carbocisteine.

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 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 phase¹⁸ .

End of life care

Inevitably, the disease will progress and 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.

Complications

• 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.

Prognosis

• MND is usually a rapidly progressive and fatal disease but the rate of progression is variable¹⁹ .

• Median survival is two to four years²⁰ .

• 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.

• Chronic neuromuscular respiratory failure is the most common cause of morbidity and mortality, due to progressive diaphragm weakness²¹ .

• The following prognostic factors are associated with shorter survival if they are present at diagnosis¹ :
  

  • Speech and swallowing problems (bulbar presentation).

  • Weight loss.

  • Poor respiratory function.

  • Older age.

  • Lower Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS or ALSFRS-R) score.

  • Shorter time from first developing symptoms to time of diagnosis.

• There appears to be a small subgroup of patients (5-10%) surviving for a decade or more⁷ .
  .