Primary Types of Motor Neuron Disease
Motor neuron diseases (MND) are a group of neurodegenerative disorders characterized by the degeneration of upper motor neurons, lower motor neurons, or both, with amyotrophic lateral sclerosis (ALS) being the most common type, representing approximately 85% of all cases. 1
Classification of Motor Neuron Diseases
Amyotrophic Lateral Sclerosis (ALS): Characterized by degeneration of both upper and lower motor neurons in the brain and spinal cord along the corticospinal tracts. It is the most common motor neuron disease, representing approximately 85% of all cases. The majority of cases are sporadic (85-90%) with an annual incidence of 1-2/100,000 and median survival of 3-4 years after symptom onset. 1
Primary Lateral Sclerosis (PLS): A neurodegenerative disorder characterized by progressive degeneration of only the upper motor neurons, leading to gradually progressive symptoms affecting central motor systems. PLS has a slower progression compared to ALS and generally better prognosis. 2
Progressive Muscular Atrophy (PMA): Involves degeneration of only the lower motor neurons, leading to progressive muscle weakness and atrophy without upper motor neuron signs. 3
Progressive Bulbar Palsy (PBP): A variant that primarily affects the bulbar muscles first, causing difficulties with speech, swallowing, and other functions controlled by lower cranial nerves. 3
Pseudobulbar Palsy: Characterized by upper motor neuron dysfunction affecting the bulbar region, causing symptoms like emotional lability, dysarthria, and dysphagia. 1
Clinical Presentation and Diagnostic Features
ALS: Typically presents with a combination of hypertonicity and hyperreflexia (upper motor neuron degeneration) and muscle fasciculations, weakness, and atrophy (lower motor neuron degeneration). 1
PLS: Presents primarily with spasticity, hyperreflexia, and weakness without significant muscle atrophy or fasciculations. 2
PMA: Characterized by progressive muscle weakness, atrophy, and fasciculations without upper motor neuron signs. 3
Diagnostic Testing: Electromyography (EMG) and nerve conduction velocity (NCV) studies are cornerstone tests for diagnosing motor neuron diseases, particularly ALS, as they can detect lower motor neuron degeneration. 3
Imaging in Motor Neuron Disease
MRI of the brain without IV contrast is the optimal initial imaging modality for patients with suspected motor neuron disease, primarily to exclude other conditions with similar clinical presentations rather than to confirm the diagnosis. 1, 3
Common MRI findings in ALS include abnormal T2/FLAIR signal in the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles. 3
Spine MRI may show abnormal T2/STIR signal in the anterior horns ("snake eyes" appearance), though this finding is not specific for ALS and may only appear later in the disease course. 1, 3
Genetic Factors
Familial ALS: Clear genetic inheritance has been demonstrated in a minority of patients with familial ALS. Genetic testing for ALS-associated genes (e.g., C9orf72, SOD1, FUS, TARDBP) should be considered, especially in cases with family history. 3, 4
C9orf72 hexanucleotide repeat expansion is the most common mutation, accounting for 10% of all Western hemisphere ALS. 5
Management Approaches
Evidence-based management involves riluzole, multidisciplinary care, provision of noninvasive ventilation and gastrostomy, and symptomatic treatments. 6
Tofersen should be offered to treat SOD1-MND, while edaravone and Relyvrio are approved treatments in the USA. 6
Supportive care requires a multidisciplinary approach in the absence of curative or disease-modifying therapy for most forms of MND. 4
Pathophysiology
Neuronal degeneration in ALS appears to be a form of apoptotic cell death that may occur by an abnormal programmed cell death mechanism. 7
Multiple pathogenic mechanisms have been identified, including altered RNA processing and protein degradation pathways, suggesting that motor neuron degeneration may be a common final pathway with several upstream causes. 5
Key Clinical Considerations
Early diagnosis is challenging due to the variable and complex features of these conditions, with an average one-year delay from first symptoms to diagnosis in ALS. 5
Disease progression is heterogeneous - while half of ALS patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. 5
Differential diagnosis is extensive and includes treatable conditions, making specialist neurological opinion essential in suspected cases. 4