Motor Neuron Disease

Question 1

What is motor neuron disease?
Examples of MND (4)

Answer 1

Progressive disorder of neuronal loss at all levels of motor system from cortex to brainstem (UMNL) and anterior horn cells of spinal cord (LMNL)

Examples:
1. Amyotrophic lateral sclerosis (ALS): mixed UMM LMN
2. Progressive muscular atrophy/SMA: LMN
3. Primary lateral sclerosis: UMN
4. Progressive bulbar palsy: bulbar involvement
5. Hereditary spastic paraplegia (HSP): UMN
6. Multifocal motor neuropathy: LMN

Question 2

Pathophysiology of motor neuron disease?

Answer 2

Death of both upper corticospinal motor neurons and lower motor neurons

1. Excitotoxicity
   - Glutamate supraphysiological concentration
   - Others: AMPA, kainite
   - Triggers excessive calcium influx into motor neurons, increased intraneuronal cascade leading to production of excessive free radicals -> cell death
   - Eg: riluzole (glutamate release inhibitor) shown some effectiveness as treatment
2. Free radicals
   - Imbalance of anti-oxidants (such as SOD1 gene mutations) leading to excessive free radicals

Question 3

Genetics of motor neuron disease

Answer 3

Most cases are sporadic (5-10% familial - usually AD)
- SOD1 gene (chromosome 21) - AD
- ALS2 gene (chromosome 2) - AR
- SETX gene (chromosome 9) - AD
- VAPB gene (chromosome 20) - AD
- DCTN1 gene (chromosome 2) - AD

Others:
- Angiogenin (chromosome 14)
- VEGF (chromosome 6)
- Survival motor neuron (chromosome 5)
- Neurofilament protein (chromosome 22)
- Charged multivesicular body protein 2B (chromosome 2)

Question 4

What is fasciculation?
What conditions can cause fasciculations?

Answer 4

Spontaneous firing of large motor units formed by branching fibres of surviving axons that are striving to innervate denervated muscle fibres

Conditions that cause fasciculations
1. Post-exercise
2. Electrolyte deficiency (hypokalaemia, hypomagnesaemia)
3. Thyrotoxic myopathy
4. Cervical spondylosis
5. Syringomyelia
6. HSMN (CMT)
7. Acute poliomyelitis
8. Neuralgic amyotrophy
9. Syphilitic amyotrophy
10. Post-tensilon
11. Benign giant fasciculation
12. SMA
13. Drugs - clofibrate, lithium, salbutamol

Question 5

Clinical course of motor neuron disease

Answer 5

1. Onset: 60 years
2. Segmental progression - from 1 limb to another
3. Mean survival: 3-5 years
4. Respiratory failure due to diaphragmatic weakness as main cause of death

Question 6

What are the features of poor prognosis in MND?

Answer 6

1. Older age
2. Female
3. Bulbar onset

Question 7

Management of patient with MND

Answer 7

1. Multidisciplinary team - Neurology, PT OT ST, Respiratory
2. Symptomatic treatment
   - Drooling: anticholinergics, hyoscine, glycopyrronium
   - Dysphagia: texture and consistency modification, PEG tube
   - Speech and language therapy
   - Emotional lability: amitriptyline, lithium, levodopa, SSRI
   - Fasciculation: phenytoin, CBZ, diazepam
   - Spasticity: baclofen
   - Limb weakness: PT OT, walking aids
   - Respiratory weakness: NIV
   - Pain: analgesia, PT OT
3. Riluzole
   - Does not improve symptoms or prognosis
   - 3 month increase in survivability only

Question 8

To do: case presentation
Differential diagnosis

Question 9

ALS

T2 MRI - deheneration of corticospinal tract (hyperintensity)

Answer 9

Asymmetric weakness -> symmetrical
Distal > proximal
Cramps and volitional movement
Fasciculations
Progressive wasting
Extensor > flexor
Spastic resistance
Hyperreflexia

Bulbar involvement - swallowing difficulty, facial and tongue, dysarthria, excess weep or laughing
Respiratory
Concurrent FTD

Question 10

Investigations

Answer 10

1. MRI brain and spinal cord
2. Lumbar puncture
3. NCS, EMG
4. Genetic testing

Question 11

Caveats and atypical presentation to consider for differential diagnosis

Answer 11

1. Limited to either UMN or LMN
2. Absence of cranial nerve features
3. Involvement of non-motor neurons
4. Motor neuronal conduction block on electrophysiological testing
5. Consider mimics: lead poisoning, thyrotoxicosis, MMF, poliomyelitis, cervical cord compression