What are the typical presentation, differential diagnosis (ddx), investigations (invx), and management (mx) of Motor Neuron Disease (MND)?

Motor Neuron Disease: Presentation, Differential Diagnosis, Investigation, and Management

Typical Presentation of Motor Neuron Disease

Motor Neuron Disease (MND) is characterized by progressive muscle weakness due to degeneration of upper and lower motor neurons, with amyotrophic lateral sclerosis (ALS) being the most common form, typically leading to death from respiratory failure within 2-5 years of symptom onset. 1

Signs and Symptoms

• Upper Motor Neuron (UMN) Signs:

  • Spasticity
  • Hyperreflexia
  • Pathological reflexes (e.g., Babinski sign)
  • Pseudobulbar affect

• Lower Motor Neuron (LMN) Signs:

  • Muscle weakness and atrophy
  • Fasciculations
  • Hyporeflexia
  • Flaccidity

• Common Presenting Features:

  • Asymmetric limb weakness (70-80% of cases)
  • Bulbar symptoms (speech and swallowing difficulties) (20-30% of cases)
  • Respiratory symptoms (rare at presentation)
  • Cramps and fasciculations
  • Progressive functional decline

• Disease Variants with Distinct Characteristics:

  Feature	ALS	PMA	PLS
  Motor neuron involvement	Both UMN and LMN	Primarily LMN	Primarily UMN
  Progression rate	Rapid (2-5 years)	Intermediate	Slow (>10 years)
  Gender predominance	Slight male	Strong male	No clear predominance
  Muscle tone	Mixed (spastic/flaccid)	Flaccid	Spastic
  Reflexes	Mixed (increased/decreased)	Decreased/absent	Increased

• Atypical Variants:

  • Flail-arm syndrome
  • Flail-leg syndrome
  • Facial-onset sensory and motor neuronopathy (FOSMN)
  • Finger extension weakness and downbeat nystagmus (FEWDON-MND)
  • Long-lasting and juvenile MND-ALS 2

Differential Diagnosis

• Structural Lesions:

  • Cervical myelopathy
  • Syringomyelia
  • Foramen magnum lesions

• Inflammatory Conditions:

  • Multiple sclerosis
  • Multifocal motor neuropathy with conduction block
  • Chronic inflammatory demyelinating polyneuropathy
  • Myasthenia gravis

• Metabolic/Toxic:

  • Hyperthyroidism
  • Heavy metal poisoning (lead, mercury)
  • Hexosaminidase deficiency
  • Hyperparathyroidism

• Other Neurodegenerative Disorders:

  • Kennedy's disease (X-linked spinobulbar muscular atrophy)
  • Adult-onset spinal muscular atrophy
  • Inclusion body myositis
  • Post-polio syndrome

• Infectious:

  • HIV-associated motor neuronopathy
  • HTLV-1 associated myelopathy
  • Lyme disease

Investigations

1. Clinical Assessment:

   • Detailed neurological examination focusing on both UMN and LMN signs
   • Assessment of bulbar function
   • Respiratory function assessment

2. Essential Investigations:

   • Electromyography (EMG) and nerve conduction studies (NCS) to demonstrate:
     • Active and chronic denervation in multiple body regions
     • Normal sensory nerve conduction
   • MRI of brain and spinal cord to exclude structural lesions
   • Respiratory function tests (FVC, SNIP)
   • Blood tests to exclude mimics:
     • Full blood count
     • Electrolytes, liver and renal function
     • Thyroid function
     • Calcium, phosphate
     • Creatine kinase
     • Vitamin B12 and folate
     • Inflammatory markers (ESR, CRP)
     • Autoimmune screen (ANA, ENA, ANCA)
     • HIV, HTLV-1 (in endemic areas)

3. Specialized Tests (when indicated):

   • Genetic testing (especially in familial cases)
   • Lumbar puncture
   • Muscle biopsy
   • Neurofilament levels (emerging biomarker) 3

Management

Management requires a multidisciplinary approach focusing on symptom control, maintaining quality of life, and supporting respiratory function. 1, 4

Disease-Modifying Treatments:

1. Riluzole:

   • Only modestly effective, prolongs survival by 3-4 months 4
   • Standard treatment for ALS

2. Edaravone:

   • FDA-approved in the US
   • Administered as intravenous infusion
   • Initial treatment cycle: daily dosing for 14 days, followed by 14-day drug-free period
   • Subsequent cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods 5
   • Not approved in UK/Europe due to insufficient evidence 3

3. Tofersen:

   • For SOD1-MND specifically 3

Symptomatic Management:

1. Respiratory Support:

   • Regular monitoring of respiratory function
   • Non-invasive ventilation (NIV) when appropriate:
     • Improves quality of life and prolongs survival 4
     • Particularly beneficial in patients with good or moderately impaired bulbar function
   • Invasive ventilation via tracheostomy in selected cases 1

2. Nutritional Support:

   • Regular assessment of swallowing function
   • Dietary modifications for dysphagia
   • Gastrostomy tube placement when appropriate:
     • Consider when weight loss >10% of baseline
     • Before vital capacity falls below 50% predicted 1, 4

3. Symptom Control:

   • Pain management: Address musculoskeletal pain, neuropathic pain, spasticity, and cramps
   • Spasticity: Baclofen, tizanidine, or botulinum toxin
   • Sialorrhea: Anticholinergics, botulinum toxin injections
   • Emotional lability: SSRIs or TCAs
   • Fatigue: Energy conservation techniques

Palliative Care:

• Early integration of palliative care is essential, not just at end-of-life 1
• Advance care planning discussions regarding:
  • Resuscitation status
  • Ventilatory support options
  • Artificial nutrition and hydration
  • Preferred place of death
• Community palliative care programs to support home care
• Hospice enrollment when appropriate

Multidisciplinary Team:

A comprehensive team should include:

• Neurologist
• Palliative care specialist
• Respiratory therapist
• Nutritionist
• Speech-language pathologist
• Physical/occupational therapist
• Social worker/psychologist
• Home care coordinator 1

Prognosis

• Median survival: 2-5 years from symptom onset
• Key prognostic factors:
  • Age at onset (older age = worse prognosis)
  • Site of onset (bulbar onset = worse prognosis)
  • Rate of progression
  • Weight loss and lower BMI
  • Respiratory function decline 1
• Approximately 10% of patients survive beyond 10 years