What is Motor Neurone Disease (MND)?

Motor Neurone Disease (MND)

Motor Neurone Disease (MND) is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord, leading to progressive muscle weakness, disability, and ultimately death, typically due to respiratory failure.

MND is characterized by progressive degeneration of both upper and lower motor neurons, resulting in muscle weakness, atrophy, and eventual respiratory failure, with most patients dying from pulmonary infections or respiratory failure within 2-5 years of diagnosis.

Types and Clinical Manifestations

MND encompasses several clinical variants:

• Amyotrophic Lateral Sclerosis (ALS): The most common form (65-75% of cases), presenting in two main patterns 1:

  • Spinal/limb onset (65-75% of patients): Initial weakness in limbs
  • Bulbar onset (25-35% of patients): Initial speech and swallowing difficulties, associated with shorter survival

• Primary Lateral Sclerosis: Predominantly upper motor neuron involvement

• Progressive Muscular Atrophy: Predominantly lower motor neuron involvement

• Progressive Bulbar Palsy: Primarily affecting bulbar muscles

• Atypical variants including flail-leg syndrome, flail-arm syndrome, and facial-onset sensory and motor neuronopathy (FOSMN) 2

Clinical Features

Upper Motor Neuron Signs 1:

• Hypertonicity/spasticity
• Hyperreflexia
• Positive Babinski sign
• Proximal weakness in lower limbs
• Preserved muscle bulk

Lower Motor Neuron Signs 1:

• Hypotonia
• Hyporeflexia or areflexia
• Muscle fasciculations
• Muscle atrophy
• Characteristic pattern of weakness
• Muscle cramps

Key Diagnostic Features:

• Progressive spread of symptoms from one body region to others
• Absence of sensory abnormalities
• Combined upper and lower motor neuron signs
• No cognitive impairment in most cases (though frontotemporal dementia can co-occur)

Pathophysiology

MND is primarily caused by genetic mutations, with over 100 different mutant genes identified 3. The pathophysiological mechanisms include:

• Protein aggregation
• Oxidative stress
• Mitochondrial dysfunction
• Glutamate excitotoxicity
• Impaired axonal transport
• Neuroinflammation

Diagnosis

Diagnosis is primarily clinical, supported by:

1. Clinical assessment demonstrating both upper and lower motor neuron signs 1

2. Electrophysiological studies:

   • EMG showing active denervation, chronic denervation/reinnervation, and fasciculations in multiple body regions
   • Nerve conduction studies to distinguish between upper and lower motor neuron pathology

3. Neuroimaging:

   • Brain MRI without contrast to evaluate upper motor neuron disorders
   • Spinal MRI without contrast when myelopathy is suspected
   • Primarily used to exclude other conditions with similar presentations

4. Laboratory tests:

   • Serum creatine kinase (may be mildly elevated)
   • Thyroid function tests (to rule out hypothyroidism)

Prognosis

Prognostic factors include 1:

• Age at onset (older age associated with shorter survival)
• Site of onset (bulbar onset has worse prognosis)
• Weight loss and lower BMI (associated with shorter survival)
• Rate of respiratory function decline

Management

Management is multidisciplinary and primarily supportive:

Respiratory Management:

• Regular assessment of respiratory function
• Non-invasive ventilation when indicated
• Management of secretions

Nutritional Support:

• Swallowing assessment using videofluoroscopy or fiberoptic endoscopic evaluation of swallowing (FEES) 1
• Early gastrostomy placement when dysphagia progresses

Symptomatic Treatment:

• Spasticity management
• Pain control
• Management of excessive salivation
• Treatment of emotional lability

Palliative Care:

• Should be adopted from the time of diagnosis 1
• Early referral to palliative services before communication becomes limited
• End-of-life care planning

Disease Course

MND typically progresses through several stages 1:

• Early stage: Initial symptoms, diagnosis
• Middle stage: Increasing disability, need for assistive devices
• Advanced stage: Significant disability, respiratory compromise
• Terminal stage: Complete dependency, respiratory failure

Contrary to popular belief, death from choking is rare, and the final stages are usually peaceful 4.

Cardiac Considerations

While MND primarily affects motor neurons, cardiac involvement can occur in some cases, particularly:

• In amyotrophic lateral sclerosis variants of MND, diaphragm involvement may precede locomotor disability 5
• Sleep-disordered breathing may arise from respiratory muscle weakness 5
• Cardiac complications are more common in certain genetic forms of MND 5

Recent Developments

Recent advances include 6:

• Discovery of neurofilaments as MND biomarkers
• Development of platform trials for testing multiple therapies
• Novel therapeutic approaches targeting specific genetic mutations