Spinal amyotrophic lateral sclerosis (spinal ALS), also known as classic ALS or Charcot's disease, is the most common form of ALS, representing approximately 65-70% of all cases. This variant initially affects the limbs, particularly the upper extremities, with involvement of both upper motor neurons (corticospinal tract) and lower motor neurons (anterior horn cells).
- Prevalence: 4-6 per 100,000 population
- Incidence: 1-2 per 100,000 annually
- Age of onset: Typically 55-60 years (younger than bulbar onset)
- Gender distribution: Male predominance (1.5-2:1)
- Geographic variation: Higher incidence in some populations (e.g., Guam, Kii Peninsula)
| Gene | Inheritance | Frequency | Phenotype |
|------|-------------|-----------|-----------|
| C9orf72 | Autosomal dominant | ~40% of familial | Earlier onset, bulbar involvement |
| SOD1 | Autosomal dominant | ~15-20% | Aggressive, limb onset |
| TARDBP | Autosomal dominant | ~5% | Variable |
| FUS | Autosomal dominant | ~5% | Younger onset |
| ANG | Autosomal dominant | Rare | Variable |
- No clear family history
- Similar genetic susceptibility factors
- Environmental factors may play a role
- De novo mutations possible
flowchart TD
A["Genetic Susceptibility"] --> B["Environmental Triggers"]
B --> C["Shared Pathways"]
C --> D["RNA Processing Dysregulation"]
C --> E["Mitochondrial Dysfunction"]
C --> F["Oxidative Stress"]
C --> G["Excitotoxicity"]
C --> H["Neuroinflammation"]
C --> I["Cytoskeletal Abnormalities"]
D --> J["Motor Neuron Degeneration"]
E --> J
F --> J
G --> J
H --> J
I --> J
J --> KUMN + L["MN Signs"]
K --> L["Clinical ALS Phenotype"]
-
TDP-43 proteinopathy
- TDP-43 inclusions in ~95% of ALS cases
- Cytoplasmic mislocalization
- Loss of nuclear function
- RNA splicing disruption
-
RNA metabolism
- Abnormal RNA splicing
- Impaired RNA transport
- Stress granule formation
- Translation dysregulation
-
Excitotoxicity
- Glutamate excess
- AMPA/Kainate receptor overactivation
- Calcium influx
- Mitochondrial damage
-
Mitochondrial dysfunction
- Energy failure
- ROS production
- Apoptosis initiation
- Axonal transport defects
-
Neuroinflammation
- Microglial activation
- Astrogliosis
- Cytokine release
- Autoimmune components
- Motor cortex: Betz cell loss, corticospinal tract degeneration
- Spinal cord: Anterior horn cell loss, gliosis
- Cranial nerve nuclei: XII (hypoglossal) involvement in some cases
- Extrapyramidal structures: Substantia nigra involvement
- Frontal cortex: TDP-43 pathology in some cases
- Weakness: Often asymmetric, starting in intrinsic hand muscles
- Atrophy: Thenar/hypothenar wasting
- Fasciculations: Early muscle twitches
- Clumsiness: Dropping objects, difficulty with fine motor tasks
- Cramps: Painful muscle contractions
- Foot drop: Difficulty with heel walking
- Gait disturbance: Stumbling, tripping
- Leg weakness: Proximal or distal
- Cramps: Especially at night
| Phase |
Timeline |
Characteristics |
| Prodromal |
Months 0-6 |
Subtle weakness, clumsiness |
| Early |
Months 6-18 |
Focal deficits, spreading to adjacent regions |
| Middle |
Months 18-36 |
Generalized weakness, respiratory involvement |
| Late |
Months 36-60 |
Severe quadriparesis, complete dependence |
| End-stage |
>60 months |
Locked-in state, respiratory failure |
- Hyperreflexia
- Pathological reflexes (Babinski, Hoffmann)
- Spasticity
- Pseudobulbar affect
- Muscle weakness
- Atrophy
- Fasciculations
- Hyporeflexia/areflexia
- Diaphragmatic weakness: Usually occurs 1-3 years after onset
- Nocturnal hypoventilation: Early sign
- Forced vital capacity (FVC) decline: ~2-4% per month
- Sniff nasal pressure: Sensitive measure of respiratory muscle strength
| Feature |
Frequency |
| Pain |
40-60% |
| Cognitive change |
15-20% |
| Frontotemporal dementia |
5-10% |
| Sensory symptoms (non-specific) |
10-20% |
Definite ALS:
- Clinical evidence of UMN signs in 3 regions
- OR clinical evidence of UMN in 1+ regions AND LMN in 3+ regions
Probable ALS:
- Clinical evidence of UMN and LMN signs in 2 regions
- UMN signs above LMN signs
Possible ALS:
- Clinical evidence of UMN signs in 1+ regions
- OR LMN signs in 2+ regions
Suspected ALS:
- Combined clinical and EMG criteria
- Earlier diagnosis possible
- Fasciculation potentials = evidence of denervation
¶ Gold-Standard Tests
| Test |
Purpose |
| EMG |
Confirm diffuse denervation |
| Nerve conduction |
Exclude neuropathy |
| MRI brain/cervical |
Exclude structural disease |
| Genetic testing |
C9orf72, SOD1, TARDBP, FUS |
| Pulmonary function |
Baseline and monitoring |
- Neurofilament light chain (NfL): Prognostic marker
- Phosphorylated neurofilament heavy chain (pNfH): Disease progression
- CSF/total tau: Disease staging
- Genetic panels: Diagnostic confirmation
-
Riluzole (1995)
- Reduces glutamate excitotoxicity
- Extends survival by 2-3 months
- Side effects: Nausea, liver dysfunction
-
Edaravone (2017)
- Antioxidant
- Slows functional decline
- IV infusion cycles
- Selected patients
| Symptom |
Treatment |
| Muscle cramps |
Quinine, mexiletine, baclofen |
| Spasticity |
Baclofen, tizanidine, benzodiazepines |
| Sialorrhea |
Glycopyrrolate, botulinum toxin |
| Pseudobulbar affect |
Dextromethorphan/quinidine |
| Pain |
Analgesics, gabapentinoids |
| Depression/anxiety |
SSRIs, counseling |
- Neurologist (ALS specialist)
- Pulmonologist
- Dietitian
- Physical therapist
- Occupational therapist
- Speech-language pathologist
- Social worker
- Mental health professional
-
Respiratory care
- Baseline FVC monitoring (monthly)
- Non-invasive ventilation (BiPAP) when FVC <50%
- Cough assist device
- Secretion management
-
Nutritional support
- Weight monitoring
- Caloric intake optimization
- PEG placement when swallow unsafe
- Dietary supplementation
-
Speech and communication
- Regular assessment
- Voice banking
- AAC devices
- Communication partner training
-
Physical therapy
- Range of motion
- Transfer assistance
- Fall prevention
- Equipment provision
| Approach |
Status |
Target |
| C9orf72 ASO |
Phase 1/2 trials |
C9orf72 expansion |
| SOD1 ASO (tofersen) |
Approved (2023) |
SOD1 mutations |
| FUS ASO |
Phase 1/2 trials |
FUS mutations |
| Stem cell therapy |
Phase 1/2 trials |
Motor neuron replacement |
| Gene therapy |
Various trials |
Multiple |
- Median survival: 2-4 years from symptom onset
- 5-year survival: 10-20%
- 10-year survival: 2-5%
- 20-year survival: <1%
| Factor |
Effect |
| Younger age at onset |
Better prognosis |
| Limb onset vs. bulbar |
Better prognosis |
| Longer diagnostic delay |
Better prognosis |
| Preserved respiratory function |
Better prognosis |
| C9orf72 expansion |
Variable |
| SOD1 mutations |
Variable |
- Respiratory failure (most common): 50-60%
- Pneumonia/aspiration: 20-30%
- Cardiovascular: 10-15%
- Cachexia: 5-10%
- Pulmonary embolism: 5%
- Neurofilaments: NfL, pNfH for diagnosis/prognosis
- Genetic markers: C9orf72, others
- Imaging: MRI, PET biomarkers
- Electrophysiology: Quantitative EMG markers
Active areas:
- Gene-targeted therapies
- Combination approaches
- Symptom-specific interventions
- Biomarker-driven trials
- Recognition of ALS-FTD spectrum
- Precision medicine approaches
- Early intervention strategies
- Multi-omics integration
This section needs to be populated with recent publications.
- ALS genetics and biomarkers
- Neuroprotective therapeutic approaches
- Clinical trial updates