Motor Neuron Disease Flashcards
What does Motor Neuron Disease refer to?
A group of conditions characterised by a degeneration of lower motor neurons and/or upper motor neurons
Lower motor neurons
Those that have cell bodies in the cranial nerve nuclei or in the anterior horn of the spinal cord and synapse directly on muscle
Upper motor neurons
Those that have cell bodies in the brain and synapse on lower motor neurons
Motor Neuron Diseases of the UMN
Primary Lateral Sclerosis
Psuedobulbar palsy
Motor Neuron Diseases of the LMN
Progressive muscular atrophy
Spinal muscular atrophy
Progressive bulbar palsy
Kennedy disease
Motor neuron diseases of the UMN and the LMN
Amyotrophic Lateral Sclerosis
What does Amyotrophic mean?
No muscle nourishment
What does lateral mean?
Refers to the areas in person’s spinal cord where portions of the nerve cells that signal and control the muscle are located
What is sclerosis?
Scarring of the affected tissue
Progression of ALS
Gradually muscles under voluntary control are affected
Individuals lose strength, ability to sleep, eat, move and breath.
Most people with ALS die of respiratory failure within 3 to 5 years of onset
ALS affects nerve cells responsible for controlling _ muscle movement
Voluntary
Motor neurons are the link between the brain and voluntary muscles.
What happens to upper and lower MN in ALS?
They degenerate and die
Unable to function, the muscles degenerate
ALS subtypes
Classical ALS
Primary Lateral Sclerosis (PLS)
Progressive Muscular Atrophy (PMA)
Symptoms of ALS caused by UMN
Hyperreflexia (twitching)
Spasticity (muscles are stiff and hard to move)
Slowing of movements
Symptoms of ALS caused by LMN
Weakness
Muscle atrophy
Fasciculations (spontaneous contraction or relaxation of muscles)
Established ALS risk factors
Age and family history
Proposed risk factors for ALS
Cigarette smokers
labourers engaged in agricultural work
factory work
heavy manual labour
exposure to welding or soldering
work in the plastics industry
Pathology of ALS
Cortical motor cells disappear, leading to retrograde axonal loss and gliosis in the corticospinal tract.
This gliosis results in the bilateral white matter changes
The spinal cord becomes atrophic.
The ventral roots become thin, and there is a loss of large, myelinated fibres in motor nerves.
The affected muscles show denervation atrophy.
Pathogenic mechanisms of ALS
- Glutamate excitotoxicity
- Mitochondrial dysfunction
- Protein aggregation
- Oxidative stress
- Neuroinflammation
- RNA metabolism dysregulation
- Axonal transport defects
- Epigenetic alterations
El Escorial Criteria Overview
A set of diagnostic guidelines developed for the diagnosis of amyotrophic lateral sclerosis (ALS)
El Escorial Criteria
- Possible ALS (U+LMN signs in 1 region OR UMN signs in ≥ 2 regions)
- Probable ALS (UMN signs in ≥ 1 region AND LMN signs in ≥ 2 regions)
- Possible ALS (U+LMN signs in 2 regions with at least one UMN sign rostral to LMN signs)
- Definite ALS (U+LMN signs in 3 regions)
What is the role of electromyography in MND
Detects electrical activity in muscles, revealing abnormalities indicative of motor neuron involvement, such as denervation patterns and spontaneous muscle activity
What is the importance of genetic testing in MND?
Diagnosing familial forms of MND, identifying specific mutations associated with the disease, which can inform prognosis and guide management strategies for affected individuals
How to diagnose ALS?
- Clinical and neurological exams
- MRI
- Myelogram of cervical spine
- Muscle and/or nerve biopsy
- Electromyography (EMG) and nerve conduction velocity (NCV) to measure muscle response to nervous stimulation
How is riluzole thought to reduce glutamate-induced excitotoxity?
- inhibition of glutamic acid release
- noncompetitive block of NMDA receptor mediated responses
- direct action on the voltage-dependent sodium channel
Drawbacks of Riluzole
Limited efficacy, only extends survival 2-4 months
Common adverse effects (50%)
Serious risks like liver dysfunction
High discontinuation rates because of risks
No improvement in function only survival
Side effects of Riluzole
Gastrointestinal disturbances (nausea, vomiting, diarrhea)
Fatigue
Dizziness.
Emerging gene therapies for ALS
Innovative gene therapies targeting specific genetic mutations associated with MND are under investigation, personalized treatment options?.
Enhanced supportive care models for ALS
Nutritional management and respiratory support etc, are crucial for maintaining quality of life and prolonging survival in MND patients.
Exosome-based therapies for MND
Novel strategy
Using exosomes from LPS-stimulated macrophages to skew microglia towards M2 phenotype
Microglial depletion and repopulation for MND
Inducing microglial replacement to restore homeostatic functions
Targeting specific molecules for MND
- Nicotinamide phosphoribosyl transferase (NAMPT) to inhibit pro-inflammatory microglia
- Long noncoding RNA H19 to modulate HDAC-dependent M1 microglial polarization
