26th June 2023

Motor Neurone Disease

Motor neurone disease is a group of chronic sporadic and hereditary neurodegenerative diseases characterised by axonal degeneration of neurons responsible for somatic motor function in the motor cortex, anterior horn cells, corticospinal tracts, and cranial nerve nuclei. It can affect the upper motor, lower neurons or both simultaneously. There is usually no sensory loss or sphincter disturbance.

The incidence of motor neuron disease is 2-3 in 100,000, with a prevalence of 5-7 in 100,000. The median age of onset is 60 years. Prognosis is poor, with an average life expectancy of 2 to 4 years after diagnosis. Poor prognostic markers include female gender, older age of onset, bulbar involvement, and respiratory involvement.

Aetiology

There is a genetic basis to MND which can be sporadic or hereditary. Approximately 10 percent of individuals with amyotrophic lateral sclerosis (ALS), a common form of MND, have familial disease. The estimated lifetime risk of sporadic ALS is 1 in 400 with a male to female preponderance of 3:2. Four genes, the C9ORF72 (chromosome 9 open reading frame), TARDBP (TAR DNA binding protein), SOD1 (superoxide dismutase), and FUS (fused in sarcoma) RNA binding protein) genes are associated with up to 70 percent cases of familial ALS. C9ORF72 has been associated with 40 percent cases of familial and 10 percent cases of sporadic MND. C9ORF72 mutations, which lead to a hexanucleotide repeat expansion, have also been found in cases of fronto-temporal dementia, suggesting a link or possibly spectrum between the diseases. The neuropathological hallmark of MND is the presence of ubiquitinated proteinaceous inclusions in motor neurons containing TDP-43 (transactive response DNA binding protein 43), together with skeletal muscle and cortical motor atrophy.

Clinical features

Phenotypes are based upon the site of origin (spinal/limb versus bulbar/respiratory) and the severity of neurological involvement, which can be characterised by:

• asymmetrical versus symmetrical
• proximal versus distal
• upper versus lower limb predominance
• degree of upper motor to lower motor neuron signs
• presence or absence of bulbar symptoms
• presence or absence of respiratory involvement

The four large subtypes of MND are:

1. Amyotrophic lateral sclerosis (ALS)
   • Typically limb onset, progressing asymmetrically from distal to proximal muscles
   • Loss of motor neurons in cortex and anterior horn results in mixed upper motor neuron (hyperreflexia and spastic weakness) and lower motor neuron signs (flaccid paralysis, muscle atrophy, hyporeflexia/areflexia, and fasciculations).
   • Bulbar involvement is documented in one fifth to one third of presentations, along with respiratory and psychiatric symptoms (frontotemporal dementia).
   • Typical clinical presentation is with distal asymmetrical manifestations such as difficulty turning keys/door knobs, writing, unsteady gait, or frequent falls.
   • A hypercatabolic state can develop disproportionately to physical activity, the cause of which is not yet known.
2. Progressive bulbar palsy
   • This is typically a bulbar-onset ALS which has rapid progression and worse prognosis; there are reports of an isolated bulbar palsy which is more slowly progressive and has better prognosis.
   • Affects CN 9 to 12, causing a bulbar palsy with lower motor neuron signs, e.g. flaccid fasciculating tongue, quiet nasal speech, absent jaw jerk, and loss of gag reflex.
   • Mimics include Guillain Barré syndrome, myasthenia gravis and central pontine myelinolysis.
   • Classic progressive bulbar palsy may then develop into ALS phenotype as above.
3. Progressive muscular atrophy
   • Purely anterior horn cell lesion resulting in lower motor neuron phenotype.
   • Asymmetrical distal to proximal progression, typically asymmetric weakness with distal limb atrophy
   • Rare cause of MND (5%).
   • Better prognosis with a slower rate of progression.
4. Primary lateral sclerosis
   • Loss of Betz cells in motor cortex – primarily upper motor neuron signs
   • Spinal motor neurons not affected, therefore no muscle atrophy
   • Marked spastic paraparesis with pseudobulbar palsy, with stiffness
   • Rarest form of MND (1-3%)
   • Slowly progressive

Investigations

The variability of clinical findings in MND and the lack of a clear biological diagnostic marker can make absolute diagnosis a challenge. The El Escorial and Airlie House diagnostic criteria for ALS include:

• Presence of lower motor neuron degeneration by clinical, electrophysiological, or neuropathological evidence.
• Presence of upper motor neuron degeneration by clinical evidence.
• Progressive spread of signs and symptoms within a region to another region determined by history and examination.
• The absence of electrophysiological, pathological, and neuroimaging evidence of other disease processes that might explain the observed clinical signs.

Thus, investigations are focused on both excluding other pathology and identifying criteria that would fulfil an MND diagnosis. Tests to exclude other pathologies may include thyroid function tests, B12/folate, CK, immunoglobulins, serum electrophoresis, virology, receptor antibodies and lumbar puncture. Imaging may include MRI head and spine, and functional tests such as nerve conduction studies and electromyography. A muscle biopsy can also be considered. Neurofilament light peptide and phosphorylated neurofilament heavy neuropeptides in cerebrospinal fluid (CSF) have been associated with ALS, but these are not specific and can also be found in Alzheimer’s dementia and multiple sclerosis.

Management

Management of MND is with a multi-disciplinary approach, a combination of the neurologist, physiotherapy, occupational therapy, dietitian, specialist nurse, family, and community team.

Disease modifying modalities include Riluzole, an NMDA (N-methyl-D-aspartate) receptor antagonist with antiglutamatergic action, which has been found to improve survival by 3 months. Edaravone is a newer drug; it is a member of the substituted 2-pyrazolin-5-one class and is thought to act as an antioxidant with a neuroprotective effect, impeding disease progression. Where there is respiratory involvement, non-invasive ventilation overnight has been shown to extend survival and improve quality of life.

Symptomatic treatment includes managing oral secretions with hyoscine, amitriptyline, propantheline, botulinum into parotid glands, and preventing thick bronchial secretions with carbocisteine and nebulised saline. Spasticity can be managed with tizanidine (α2 receptor agonist), baclofen, physiotherapy and botulinum injections. Pain management is with analgesia, such as NSAIDs, opioids, and cannabinoids, gabapentinoids, and tricyclic antidepressants.

Due to the hypercatabolic state and dysphagia associated with MND, nutrition is of high importance and feeding via a gastrostomy tube can be considered. Pressure sores and damage should be monitored closely, and VTE prophylaxis considered. Constipation treatment with laxatives, and bladder control with oxybutynin, tolterodine or a long-term catheter can be considered. The need for psychological support, social support and help with communication cannot be overstated.