Motor Neurone Disease

• Sporadic, progressive neurodegenerative disease
• Typically presents in sixth and seventh decade
• Familial in approximately 5% of cases
• May present with mixed upper and lower motor neurone signs (most common, classic presentation)
  • Usually initially focal, with particular groups of muscles affected
  • Patterns
    • Limb (most common): asymmetrical distal weakness, with wasting of the small muscles of the hand, clumsiness and difficulty in turning a key, writing or opening bottles
      • Lower limb (30%): tendency to trip, foot drop, sensation of heaviness in both legs
    • Bulbar (20%): slurring of speech with wasting a fasciculation of the tongue, dysphagia
      • May also have prominent emotional lability
    • Respiratory: less common; may present with dyspnoea, orthopnoea or symptoms suggestive of obstructive sleep apnoea (frequent waking, daytime somnolence, unrefreshing sleep)
• Rarer variants
  • Primary lateral sclerosis (2%), pure upper motor neurone
  • Progressive muscular atrophy (4%), pure lower motor neurone presentation
• Spectrum of presentations results from degeneration of upper and lower motor neurones
• Death usually results from respiratory muscle weakness and ventilatory failure

Relevant physical signs

• Inspection
  • Wasting
  • Generalized fasciculations
  • Tongue fasciculations and bilateral tongue wasting
  • Feeding aids – nasogastric tube, percutaneous gastrostomy
  • Walking aids / wheelchair
  • Head drop – weakness of neck extensors
  • Ankle orthoses for food drop
• Limbs
  • Initial presentation is often with asymmetric distal wasting and weakness
  • Tone may be increased in a velocity-dependent manner (UMN involvement)
  • Reflexes are often increased (UMN involvement)
    • Hoffman’s sign may be present
    • Plantars may be extensor
    • Patients may have ankle clonus
  • Power: asymmetrical distal weakness with ascends and progresses to become bilateral
  • There are usually no cerebellar signs (if the patient is strong enough to have this tested)
  • Sensation is completely normal
• Cranial nerves
  • Eye movement are almost never involved in motor neurone disease
  • May have brisk jaw jerk
  • Patients may have weakness of facial muscles
  • Often, there is a bulbar or pseudobulbar palsy
  • Speech is slurred because of a wasted tongue, together with dysarthria
    • Bulbar palsy: indistinct, nasal speech
    • Pseudobulbar palsy: stiff, spastic tongue with slow, grunting, spastic speech
  • Palatal paralysis may occur
  • Patients may have difficulty swallowing
• Offer to examine
  • Cognition (small percentage of patients have frontotemporal dementia or cognitive impairment)
  • Respiratory function with measurement of negative inspiratory force

 Differential diagnosis

• Pure lower motor neurone presentation
  • Benign fasciculations (thyrotoxicosis, alcohol, exercise, caffeine)
  • Cramp-fasciculation syndrome
  • Multifocal motor neuropathy with conduction block (10 times rarer than MND)
    • Pure motor neuropathy
    • Male predominance, mean age of onset 40 (cc. 65 in MND)
    • Often less wasting than MND
    • Slowly progressive, asymmetrical distal weakness
    • Reflexes usually absent, but may be retained or even brisk in 20%
    • No bulbar features
    • Respiratory muscle weakness is extremely rare
    • Patients may have anti-GM1 ganglioside antibodies (50% sensitivity)
    • Supported by T2-hyperintensity of the brachial plexus on MRI
    • Early intravenous immunoglobulin may limit axonal loss and progression rate
  • Brachial neuritis
    • Often severely painful (unilateral neck, shoulder or arm) in the absence of trauma
    • 5% painless
    • Usually preceded by viral infection or vaccination
    • Followed by progressive upper limb weakness and muscle wasting which then arrests
    • Variable, slow recovery over moths to years
  • Spinobulbar muscular atrophy (Kennedy’s disease)
    • X-linked recessive disorder from trinucleotide expansion repeat in androgen receptor gene
    • Patients often present in 4^th or 5^th decade
    • Very slowly progressive symmetrical LMN syndrome
      • Often starts proximally
      • May have prominent bulbar symptoms
    • Fasciculations are extremely common, especially over the chin
    • Tongue often markedly wasted
    • Features of androgen insensitivity
      • Gynaecomastia
      • Sub-fertility
  • Motor-predominant chronic inflammatory demyelinating polyneuropathy
    • Typical course is relapsing-remitting
    • Differentiated by clear demyelination on nerve conduction studies
  • Inclusion body myositis
    • Slowly progressive, painless myopathy
    • Usually begins asymmetrically in distal upper limb or proximal lower limb
      • Weakness often most prominent in wrist and finger flexors and quadriceps
    • Often, creatinine kinase is markedly raised
    • Muscle biopsy is diagnostic: rimmed vacuoles with inflammatory change
  • Spinal muscular atrophy
    • Autosomal recessive disorder caused by defect in SMN1 (survival motor neurone) gene
    • Flaccid weakness with hypotonia and arreflexia
    • Prominent respiratory muscle weakness with weak cough
    • Marked tongue fasciculations
  • Poliomyelitis with post-polio syndrome
    • Asymmetric flaccid paraparesis of a single limb
    • Reflexes usually absent, no UMN signs
• Pure upper motor neurone presentation
  • Primary progressive multiple sclerosis
    • This presentation is more common in middle-aged men
    • Usually differentiated by demyelination on MRI
  • Hereditary spastic paraparesis
    • Genetically diverse group of disorders
    • Slowly progressive paraplegia
    • Sometimes affects dorsal column, sphincters and upper limbs
    • Often will have a positive family history
  • Vitamin B12 deficiency
    • May cause slowly-progressive myelopathy
    • Often will have dorsal column sensory signs
• Mixed upper and lower motor neurone signs
  • Cervical myelopathy
    • Patients may have sensory involvement
    • Typically, lower limbs show purely UMN signs, with mixed signs in the upper limbs
    • Widespread fasciculations are unlikely
    • Tongue fasciculations not a feature of cervical myelopathy
    • MRI will show cord compression
  • Syringomyelia
    • Upper motor neurone signs in legs, LMN in arms
    • Dissociated sensory loss to pinprick
    • May have bilateral Horner’s

Investigations

• Full blood count (anaemia of chronic disease)
• Renal function tests, serum electrolytes
• Thyroid function tests
• Syphilis screen (neurosyphilis)
• B12 levels (B12 myelopathy)
• Consider anti-GM1 ganglioside antibodies (multifocal motor neuropathy)
• Magnetic resonance imaging of the brain and spinal cord (PPMS, cervical myelopathy, syrinx)
• Nerve conduction studies to rule out multifocal motor neuropathy with conduction block
• Electromyography showing fibrillations and neurologic recruitment (denervation) of multiple muscles not innervated by a single nerve

Management

• Multidisciplinary team approach
• Patient education, with time consider referral for advanced care planning
• Dietician referral, consider nasogastric tube or percutaneous gastrostomy
• Riluzole is the only drug with a survival impact in MND (adds 3 – 4 months on average)
  • Adverse effects: nausea, headache, dizziness; rarely: interstitial lung disease, pancreatitis
• Consider nocturnal CPAP (median survival benefit of 7 months in patients with good bulbar function)
• Pseudobulbar affect (emotional lability from corticobulbar degeneration): dextromethorphan-quinidine

Summary

Sir, this patient has generalized wasting with fasciculations. Power is globally reduced. Reflexes are brisk throughout, and there is ankle clonus with upgoing plantars. Sensation is completely intact; I was unable to test for cerebellar dysfunction due to weakness. Functionally, there is a wheelchair by the bedside, implying that the patient is unable to walk. He has a nasogastric tube, which points towards a bulbar palsy. This is supported by a wasted, fasciculating tongue, and nasal, slurred speech. The most likely diagnosis is motor neurone disease. Other potential causes of mixed upper motor neurone and lower motor neurone signs include cervical myelopathy, although I would not expect a bulbar palsy, and syringomyelia or syringobulbia.