Motor Neurone Disease (MND)

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

This is a degenerative condition that affects motor neurones, namely the anterior horn cells of the spinal cord and the motor cranial nuclei.² 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.³ 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.^3,4 There is no known cure for this devastating disease that causes significant disability and/or death in a relatively short period of time in those unfortunate enough to suffer from it.

The Scottish MND register gave a crude annual incidence of 2.24 cases per 100,000 population in 1989.⁵ 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.⁶ US studies indicate a prevalence of about 5 cases per 100,000 population.^2,4

The disease tends to affect people in the fourth to seventh decades of their life, with familial cases usually occuring at the younger end of the spectrum and sporadic cases affecting older people.

Symptoms

Patients or their families often notice problems occurring in one or more of the patterns below:

• Bulbar onset – typically causes difficulty eating, drooling, dysarthria, dysphonia, choking events associated with meals, nasal regurgitation of fluids or pulmonary aspiration.
• Limb weakness – usually affects the upper limbs but may occasionally cause problems in the leg(s) (usually foot drop or gait disorder); wrist drop, impaired dexterity of the fingers, stiffness, weakness or cramping of the hands may occur; patients may notice a change in the appearance of their hands due to wasting of the intrinsic muscles.
• Fasciculations of the muscles of the limbs, or of the tongue, may be a presenting feature.
• 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.
• Upper motor neurone 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

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):⁷

• Presence of:
  • Evidence of LMN degeneration by clinical, electrophysiological or neuropathologic examination
  • Evidence of UMN degeneration by clinical examination, and
  • 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, and
  • 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. The list below shows those that may have similar clinical features:

• Diabetic amyotrophy
• Guillan-Barré syndrome
• Post-polio syndrome
• Myasthenia gravis or Lambert-Eaton syndrome
• Peripheral nerve lesions, particularly due to diabetic neuropathy
• Thyrotoxicosis with associated myopathy
• Radiculopathy or myelopathy, particularly due to cervical spondylosis
• Spinal cord tumours
• Cerebrovascular disease and stroke
• Polymyositis or dermatomyositis
• Glioma of brainstem
• HIV-associated neuropathy/myopathy/radiculopathy
• 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)
• Multifocal motor neuropathy with conduction block

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 electromyography (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.

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. 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. 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:

• 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 by themselves, 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.
• When respiratory function is impaired, physiotherapy helps to clear pulmonary secretions and maintain respiratory health.
• Tracheostomy and positive pressure ventilation may be used in patients who are no longer able to maintain adequate ventilation.
• 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 about 2 months.⁸ It may have a more significant effect on prolonging tracheostomy-free survival.⁹ It appears to be well tolerated and of greater benefit the earlier it is started in the course of the disease.¹⁰ 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.¹¹
• 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.

• 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. Death usually occurs due to respiratory failure or pneumonia due to hypoventilation. About 30% of patients survive beyond 5 years.⁴ 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.