- Seen in middle-aged and older adults (peak age 55–75 years, male:female 1.5:1, annual incidence 2:100,000). Presents with insidiously progressive, relentless muscle weakness characterized pathognomonically by the simultaneous presence of BOTH Upper Motor Neuron (UMN) and Lower Motor Neuron (LMN) signs across multiple anatomical body regions (bulbar, cervical, thoracic, lumbosacral):
- (1)LMN Signs: Fasciculations, prominent muscle atrophy, flaccidity, and severe weakness.
- (2)UMN Signs: Hyperreflexia, spasticity, clonus, extensor plantar responses (Babinski sign), and pseudobulbar affect (pathological laughing and crying).
- (3)Bulbar-Onset ALS (25%): Presents with dysarthria, dysphagia, tongue fasciculations, and rapid respiratory compromise.
- Caused by fatal, rapidly progressive neurodegenerative motor neuron disease characterized by selective degeneration and death of upper motor neurons in the motor cortex (precentral gyrus) and lower motor neurons in the brainstem and anterior horns of the spinal cord:
- (1)Molecular Pathophysiology: Cellular mislocalization and toxic cytoplasmic aggregation of ubiquitinated transactivation response DNA-binding protein 43 (TDP-43) in >95% of cases.
- (2)Genetic Mutations: C9orf72 hexanucleotide repeat expansion (most common familial cause, 40%; and sporadic, 7%), SOD1 (superoxide dismutase 1, 20%), TARDBP, and FUS.
- (3)Pathological Hallmarks: Loss of Betz giant pyramidal cells in motor cortex, marked wallerian degeneration and axonal loss of the corticospinal tracts with reactive astrocytic fibrillary gliosis and microglial lipid accumulation.
Imaging Findings
- Magnetic Resonance Imaging (Brain & Spine MRI - Diagnostic Evaluation Framework):
- –Primary Diagnostic Role: The foremost role of neuroimaging is to RULE OUT compressive, structural, and inflammatory mimics of motor neuron disease (e.g. cervical spondylotic myelopathy, multifocal motor neuropathy, cervical cord tumors, or dural arteriovenous fistulas).
- –Hallmark Corticospinal Tract (CST) T2/FLAIR Hyperintensity:
- 1.Symmetrical, bilateral, continuous high signal intensity on T2WI and FLAIR tracing along the course of the corticospinal tract, descending from the precentral subcortical white matter (corona radiata), through the posterior limb of the internal capsule (PLIC), cerebral peduncles (crus cerebri), ventral pons, and medullary pyramids.
- 2.Best evaluated on axial FLAIR: intense hyperintensity in the posterior limb of the internal capsule and cerebral peduncles.
- –The 'Motor Strip' Sign (Precentral Gyrus Hypointensity):
- 1.Marked, prominent, abnormal hypointensity along the precentral gyrus (primary motor cortex) on T2WI, T2*, and SWI / susceptibility sequences.
- 2.Caused by excessive pathological iron (ferritin) accumulation and microglial activation within the degenerating motor cortex.
- –Advanced Diffusion Tensor Imaging (DTI - Quantitative Biomarker):
- 1.Demonstrates profound, statistically significant reduction in Fractional Anisotropy (FA) and elevated Radial Diffusivity (RD) along the entire corticospinal tracts, quantitatively tracking axonal degeneration.
- Cervical Spine MRI (Mandatory Protocol):
- –Normal cord caliber initially, progressing to subtle flattening and T2 hyperintensity of the anterior horns ('owl's eyes' sign), with complete exclusion of cervical spondylotic canal stenosis or cord compression.
- Plain Spine Radiograph / Cervical MRI Exclusion Note:
- –SWI ('Motor Band Sign') & DWI / DTI: SWI shows linear hypointense blooming in the precentral gyrus cortex ('motor band sign') from microglial iron deposition, while DWI/DTI shows reduced fractional anisotropy (FA) and increased diffusivity along the degenerating corticospinal tracts.
- –Cervical Spine X-Ray & MRI: Essential to exclude severe cervical spondylotic myelopathy (osteophytes, disc-osteophyte complexes, ossification of the posterior longitudinal ligament [OPLL], and spinal canal stenosis) which can mimic mixed UMN/LMN signs.
Differential Diagnosis
| Differential Diagnosis | Key Distinguishing Features |
|---|---|
Cervical Spondylotic Myelopathy (CSM) | The most common and critical structural mimic! Spondylotic ridge, disc herniation, and ligamentum flavum thickening producing canal stenosis, cord compression, and focal intramedullary T2 cord hyperintensity; strictly lacks bulbar or intracranial corticospinal involvement. |
Multifocal Motor Neuropathy (MMN) | Pure LMN disease affecting peripheral nerves with conduction blocks; high anti-GM1 ganglioside antibodies; responds dramatically to IVIG (unlike ALS); normal brain MRI. |
Inclusion Body Myositis (IBM) | Selective weakness of finger flexors and quadriceps in older adults; muscle MRI shows asymmetric fatty infiltration and STIR edema without UMN signs or brain hyperintensities. |
Primary Lateral Sclerosis (PLS) | Pure upper motor neuron disorder without LMN signs or denervation on EMG; much slower progression, surviving decades. |
Important Points to Remember
- Diagnostic Pitfall: Diagnosing ALS on MRI without performing a cervical spine MRI to rule out cervical spondylotic myelopathy! Corticospinal tract hyperintensity on FLAIR is non-specific and can occur as a normal variant (due to dense myelination) in healthy adults, especially on 3T MRI. The mandatory safe practice in suspected ALS is to obtain a comprehensive cervical spine MRI to definitively rule out a surgically treatable compressive cervical cord myelopathy, which can cause simultaneous upper and lower limb signs.
- Crucial Review Areas:
- 1.Posterior limb of the internal capsule (PLIC) and cerebral peduncles on axial FLAIR for bilateral symmetric hyperintensity.
- 2.Precentral gyrus on SWI or T2* for abnormal hypointense iron blooming ('motor strip sign').
- 3.Cervical spinal cord on sagittal and axial T2WI: confirm total absence of mechanical spinal cord compression or intrinsic cervical cord tumor.
- 4.Tongue on coronal/sagittal T1WI in bulbar-onset cases: marked fatty atrophy and volume loss of the tongue muscles.
- Radiologist Safe Practice & Management:
- 1.Diagnostic Verification (Awaji-El Escorial Consensus Criteria): Coordinated assessment combining comprehensive brain and whole-spine MRI with extensive electromyography (EMG / nerve conduction studies) demonstrating active denervation and chronic reinnervation in >=3 body segments.
- 2.Structural Mimic Exclusion Protocol: High-resolution MRI of the cervical and lumbosacral spine to definitively rule out compressive myelopathy or radiculopathy.
- 3.Multidisciplinary Motor Neuron Disease MDT Referral: Mandatory referral to a designated Specialist MND Care Center (neurologist, specialist nurse, respiratory physician, gastroenterologist, speech therapist, occupational therapist).
- 4.Disease-Modifying Pharmacotherapy: Early initiation of Riluzole (glutamate antagonist, 50 mg BD, extends survival by 2–3 months); Edaravone (free radical scavenger) or Tofersen (antisense oligonucleotide for SOD1-mutated ALS).
- 5.Supportive & Respiratory Care: Early non-invasive positive pressure ventilation (NIV) when FVC drops <80% or nocturnal desaturation occurs (significantly extends survival and quality of life); early percutaneous endoscopic gastrostomy (PEG) or radiologically inserted gastrostomy (RIG) before FVC drops <50%.