Introduction

• MND never causes sensory problems

• ALS – Amyotropic lateral sclerosis 75% of cases of MND–this is the most common form of MND, and produces both UMN and LMN signs.
  • Both UMN and UMN signs can be present in the same muscle! – e.g. a wasted, fasciculating (LMN signs) muscle with hypereflexia (UMN sign)
  • Typically ALS consists of a progress weakness and wasting of the limbs
• PBP – progressive bulbar palsy – 25% of cases of MND – presents as problems with speech and swallowing. Many patients may have bulbar and pseduobulbar signs.
• PMA – Progressive Muscular Atrophy –typically only affects the LMN’s of the upper limbs
• SMA – Spinal muscular Atrophy – characterised by wasting and weakness of muscles.

• In many patients, as the disease progresses features of several of the different subtypes will be present in a single individual.

Epidemiology

• Incidence of 2 per 100 000
• Slight male predominance
• Usually middle aged onset (ALS)
  • PBP tends to present later, and may be slightly more prevalent in women
• 5 year survival – from the time of first diagnosis is <10%.

Aetiology

Ageing – premature ageing of some motor cells can damage and destroy these cells. This puts extra pressure on the surviving cells to perform the original functions, and the increased metabolic processes, may damage the remaining cells.
Viral infection – not much evidence for this
Chemicals – some metals (lead, celenium, mercury and manganses) have been suggested, but nothing has yet been proven
Biochemisty – possible chronic calcium deficiency plays a role – there is an association with hyperparathyroidism.

• this is also backed up by cases of gastric surgery. In such patients, MND incidence is increased, and there is reduced uptake of calcium.

Genetic – there is definitely a genetic component to some cases – and one specific gene mutation (chromosome 21) has been identified in some individuals. In such instances, there may be many cases within one family.

• It is generally thought that the degeneration of nerves seen in MND is somehow genetically programmed.

Excitotoxicity – glutamate may play a role

Pathology

• Oxidative neuronal damage
• Aggregation of abnormally large amounts of protein inside a cell
• Glutamate problems (possible involving excitotoxicity)
• Apoptosis
• Prolonged caspase activity (contributing to the apoptosis)

Clinical features

Symmetrical weakness and wasting – usually at the extremities – 75% of patients

• Wasting usually begins at the hand and spreads. It may initially be unilateral, but will soon become bilateral.
• Fasciculation – this occurs as surviving axons branch out to new motor units and attempt to innervate them. Note that fasciculation is normally a LMN sign, but in MN, there are mixed upper and lower signs.
• Cramps
• There is usually NO PAIN

Bulbar and Pseudobulbar features –25% of patients –  dysphagia and dysarthria, nasal regurg (palate weakness) and choking. Swallowing solids may be difficult, tongue may be immobile. This is progressive. It mimicks both bulbar (LMN) and pseudobulbar (UMN) palsies. For example there may be:

• Wasted, fasciculating tongue
  • Remember – fasciculations are motor units discharging spontaneously.
• Weak palate
• Eye movements are usually spared

Reflex problems – reflex may be lost, or they may become hyperreflexic:

• Loss – is the result of motor neuron problems in the anterior horn
• Hyperreflexia –due to loss of corticospinal neurons

there is no sensory loss, and sphincters are not affected.

• This helps to distinguish MND from MS and ployneuropathies.
• MND also never affects eye movements – and thus allows us to distinguish it from myasthenia gravis.

Amyotrophic lateral sclerosis (ALS)– lateral sclerosis refers to damage to the lateral corticospinal tracts – and basically means there is spastic paraparesis. Amyotrophic refers to the fact that there is loss of muscle tone. These two symptoms are rarely seen together – except in MND! There may be pyramidal weakness:

• Extensors in the upper limbs, flexors in the lower limbs
• In the USA – ALS is the term used to describe MND.

Progressive Muscular atrophy – the result of involvement of the anterior horn cells. This is often most apparent in the hands. This is sometimes called skeleton hand. There is:

• Atrophy
• Weakness – not as severe as the degree of wasting suggests.
• Fasciculation
• cramps

Dementia – in the frontotemporal region – seen in 10-30% of cases. This may initially present with language difficulties – although in some cases this can be very hard to diagnose, especially if there is also a well advanced dysphasia.
Primary lateral sclerosis – this is a specific type of MND that is confined to UMN’s. There is usually spastic tetraparesis, and in the late stages there may be pseudobulbar palsy.

Diagnosis

• UMN and LMN signs
• No sensory signs
• Progressive pattern
• Other possible signs:
  • Fasciculations
  • Normal nerve conduction

Investigations

• EMG – shows denervation and fibrillation
  • Note that denervation may not be present in primary lateral scelrosis.
• Nerve conduction studies – will appear normal. Useful to exclude multifocal neuropathy.
• MRI – will be normal. Excludes foramen magnum or spinal cord compression.
• TFT’s – to exclude hyperthyroidism
• Calcium studies – to exclude calcium/parathyroid problems
• Bloods – Creatinine kinase ↑ – due to muscle breakdown

Differentials

• Motor Neuropathy – will cause distal weakness, and LMN signs. There will be conduction block, but it can be differentiated with a test for antibodies to GM₁ glycoside.
• Spinal muscular atrophy
• Kennedy’s syndrome – x-linked inherited condition, where there is bulbar, and spinal muscle atrophy. No UMN signs.
• Hyperthyroidism and hyperparathyroidism can both result in muscle wasting and hyperreflexia.
• Pseudobulbar palsy – can be caused by cerebrovascular disease and MS.
• Conditions that exhibit both UMN and LMN signs:
  • Cervical Spondylitis
  •  Spinal tumours

• Bladder is never affected
• No sensory Signs
• Occular msucles never affected

Treatment and Prognosis

Drug therapies

• Typically increases survival by 3-5 months
  • Most effective in disease that presents with bulbar signs
• Delays the need for gastrostomy feeding and ventilatory support.
• It tends to prolong muscle function, but does not have any effect on the decline in muscle strength
• Mechanism – not really understood. It is thought thatby blocking sodium channels, the effect of glutamate is greatly reduced.
• Unwanted effects – up to 10% of patients experience nausea and fatigue, and some may be unable to tolerate treatment

Other therapies

As MND progresses, it can begin to affect the muscles of respiration, including both the diaphragm and the intercostal muscles.
It often presents at night, when the effect of gravity on the abdominal viscera is reduced, and the contents press up against the diaphragm when the patient is laid in bed.
Patients may get morning headaches from cerebral vasodilation secondary to hypoxia/hypercapnia during the night
Patients often have a weak cough due to weakness of expiratory muscles. This can mean there is an inability to clear the airway, and an increased risk of aspiration.
FVC is a reasonably reliable way of identifying those with respiratory insufficiency. Supine and erect FVC can be compared. In an MND patient, the difference between the two results may be <25%. This indicates diaphragmatic weakness. In a normal the discrepancy is less.
SNIP – sniff nasal inspiratory pressure –this measures the inspiratory ability of the patient. A bung is placed in one nostril, and a pressure probe in the other. The patient is then required to take a deep breath, and the inspiratory pressure is measured

• pressure <40cm H₂O is associated with a medican survival of 6 months. Pressure <30cm H₂O is associated with a median survival of 3 months
• All respiratory function tests are less reliable in bulbar palsy patients, as these patient may have difficulty controlling their mouth, and this can affect the pressure readings – however, SNIP is usually still acceptable.
  • Respiratory function tests and SNIP are usually performed at out-patient clinic follow-ups to assess disease progression

NIV – non-invasive ventilation – is used in patients with decreased respiratory function. It improves quality of live and can lengthen life—expectancy.

• It is typically provided in the form of BiPAP – a biphasic pressure is applied via face mask. CPAP may be used in some patients, but is not as effective.
• Compliance is reduced in patients with bulbar symptoms.
• Initially, therapy may only be used at night. As the disorder progresses, patients may require 24h assistance.

Feeding

• As bulbar and pseudobulbar palsies develop, swallowing may become especially difficult. The most common form of supplemented feeding is RIG (Radiologically inserted gastrostomy). This is performed as an inpatient procedure. Patients can continue to eat normally, and initially may only use the tube as a supplement, however, as the disease continues, they become more reliant on the tube.
• Clinicians are usually keen to have the RIG procedure performed as early as possible. The risks associated with the procedure increase as the patient loses weight – which is an obvious complication of dysphagia.

Physiotherapy and walking aids – may help with weakness
Tracheostomy and assisted ventilation – often performed, but sometimes controversial, as eventually MND leads to total paralysis.

References

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