Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases¶
Chapter 448 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 448
Key Clinical Points¶
- ALS is defined by the simultaneous involvement of upper motor neurons (UMN) and lower motor neurons (LMN).
- Median survival is 3 to 5 years, with death typically resulting from respiratory paralysis.
- C9orf72 mutations are a major genetic driver, accounting for ~45–50% of familial ALS (FALS).
- Riluzole (100 mg/d) modestly extends survival; Edaravone slows the rate of progression on disability scales.
- Sensory, bowel, bladder, and ocular motility are typically preserved in ALS.
- MRI may show high signal intensity in corticospinal tracts (Wallerian degeneration).
- Multifocal motor neuropathy with conduction block (MMCB) must be excluded as it is treatable.
- Kennedy's disease (X-linked) presents with gynecomastia and reduced fertility, distinguishing it from ALS.
- Tofersen is specifically indicated for SOD1-mediated ALS via intrathecal delivery.
- Absence of pain or sensory changes favors a diagnosis of ALS.
DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 22e): Amyotrophic lateral sclerosis (ALS) is the most common progressive motor neuron disease. • Pathologic Hallmark: Death of both lower motor neurons (LMN) and upper motor neurons (UMN). • LMN Component: Includes anterior horn cells in the spinal cord and their brainstem homologues. • UMN Component: Corticospinal motor neurons originating in layer five of the motor cortex. • Clinical Progression: While ALS may start with only one type of neuron involved, it ultimately results in the progressive loss of both. • Preserved Functions: Sensory, bowel, bladder, and ocular motility (until very late stages) are typically spared.
Functional (Psychogenic) Disorders¶
• Definition: Also known as functional neurologic symptom disorder (FND) or conversion disorder. • Prevalence: Estimated at 2–13% of patients in movement disorder clinics; more common in women. • Clinical Features: Can present as tremor, tics, dystonia, myoclonus, chorea, ballism, and parkinsonism. • Management: Education/explanation of diagnosis; primary treatment is psychological (e.g., cognitive-behavioral therapy) combined with physiotherapy.
Pathology¶
• Cellular Changes: Motor neurons undergo shrinkage and accumulation of lipofuscin. • Cytoskeleton: Early involvement of the motor neuron cytoskeleton; formation of 'spheroids' (neurofilament/protein accumulations) in proximal motor axons. • Protein Aggregates: Ubiquitin-positive aggregates, often associated with TDP43. • Neuroinflammation: Proliferation of astroglia and microglia. • Muscle Changes: Denervation leads to atrophy; early stages may show reinnervation by sprouting. • Sclerosis: Loss of corticospinal neurons results in thinning of tracts and fibrillary gliosis (lateral sclerosis).
EPIDEMIOLOGY¶
• Survival: Median survival is 3 to 5 years. • Progression: Rarely reported cases of stabilization or regression. • Mortality: Approximately 1 in 500 deaths in North America and Western Europe are due to ALS; death usually results from respiratory paralysis. • Incidence/Prevalence: Incidence of 1–3 per 100,000; prevalence of 3–5 per 100,000. • Demographics: Men are more frequently affected than women in the US and Europe. • Risk Factors: Potential links to pesticides/insecticides, silica, smoking, and military service. • Genetics: ~10% of cases are inherited as an autosomal dominant trait.
ETIOLOGY & PATHOPHYISIOLOGY¶
• General Pathogenesis: Complex process involving excitotoxicity, defective autophagy, impaired axonal transport, oxidative stress, and mitochondrial dysfunction. • Genetic Categories of ALS: 1. Protein Instability: Mutations in SOD1, ubiquilin-1/2, and p62 lead to perturbations in protein degradation. 2. RNA Processing/Transport: Mutations in C9orf73, TDP43, and FUS/TLS; C9orf72 involves an intronic hexanucleotide repeat expansion (>-30 repeats) causing translation of toxic dipeptides. 3. Axonal Cytoskeleton/Transport: Mutations in dynactin and profilin-1. • Nonneuronal Involvement: Activated microglia and astrocytes significantly influence disease course.
Familial ALS (FALS)¶
• Clinical Status: Clinically indistinguishable from sporadic ALS. • C9orf72: Accounts for ~45–50% of FALS and 5–10% of sporadic cases. • SOD1: Accounts for ~20% of FALS. • TDP43 & FUS/TLS: Each account for ~5% of FALS. • Other Genes: NEK1, optineurin, TBK1, KIF5A, TUBA4, PFN1 (each ~1%). • Special Cases: Senataxin (slowly evolving variant); Kennedy's syndrome (X-linked; mimics ALS but involves androgen receptor). • ALS/FTD Link: Over 40% of frontotemporal dementia (FTD) cases harbor C9orf72 mutations.
CLINICAL FEATURES¶
• LMN Dysfunction: ◦ Initial presentation: Insidiously developing asymmetric weakness, typically distal. ◦ Cramping: Often occurs with volitional movements in the early morning. ◦ Fasciculations: Spontaneous twitching of motor units (early sign). ◦ Hand involvement: Predominance of extensor over flexor weakness. • UMN Involvement: ◦ Hyperreflexia: Hyperactivity of muscle-stretch reflexes. ◦ Spasticity: Resistance to passive movements; stiffness often out of proportion to weakness. • Bulbar & Respiratory Symptoms: ◦ Bulbar: Difficulty with chewing, swallowing, and facial/tongue movement; dysarthria. ◦ Pseudobulbar affect: Involuntary excess in weeping or laughing. ◦ Respiratory: Early involvement can lead to death before other symptoms progress. • Progression: Moves from asymmetric to symmetric distribution across all muscle groups. • Preserved Functions: Sensory, bowel, bladder, and cognitive functions (except in cases with concurrent FTD). • Ocular Motility: Spared until very late stages.
Familial ALS (FALS) Characteristics¶
• Inheritance: Autosomal dominant. • Clinical Presentation: Identical to sporadic ALS. • Associated Disorders: Frequently co-occurs with Frontotemporal Dementia (FTD), especially in C9orf72 mutations. • Atypical Phenotypes: Some cases show prominent amyotrophy with parkinsonism-like features (linked to tau protein mutations).
DIFFERENTIAL DIAGNOSIS¶
• Rule Out Treatable Causes (Table 448-1): ◦ Structural Lesions: Cervical spinal cord/foramen magnum tumors, spondylosis, or Chiari malformation. ◦ Neuropathies: Multifocal motor neuropathy with conduction block (MMCB), motor neuropathy with paraproteinemia/cancer, and other peripheral neuropathies. ◦ Toxins/Drugs: Lead, aluminum, strychnine, phenytoin; exposure to electricity or x-irradiation. • Infectious/Inflammatory: Lyme disease (usually presents with pain/pleocytosis), viral infections (Poliomyelitis, West Nile). • Metabolic/Systemic: Hyperthyroidism, vitamin deficiencies (B12, E, folate), copper/zinc deficiency, mitochondrial dysfunction. • Specific Mimics: ◦ Kennedy's Disease: X-linked; presents with gynecomastia and reduced fertility. ◦ Benign Fasciculations: No weakness or atrophy present; excludes ALS. ◦ Chronic Traumatic Encephalopathy: Associated with TDP43 and neurofibrillary tangles.
Diagnostic Criteria for ALS¶
• Favoring ALS: ◦ Absence of pain or sensory changes. ◦ Normal bowel and bladder function. ◦ Normal radiologic studies of the spine. ◦ Normal CSF analysis. • Exclusionary Findings: ◦ Presence of motor neuronal conduction block (indicates MMCB). ◦ Evidence of involvement of non-motor neurons. ◦ Restriction to only UMN or only LMN.
DIAGNOSTIC APPROACH¶
- Initial Clinical Assessment: Identify asymmetric weakness, hyperreflexia, and fasciculations; assess for bulbar symptoms.
- Rule Out Treatable Conditions (Table 448-1): ◦ Perform MRI of head/cervical spine to rule out structural lesions (tumors, spondylosis). ◦ Order serum lead levels and 24-h urine for heavy metals if exposure is suspected. ◦ Check thyroid function, vitamin levels, and metabolic panels.
- Electrophysiology: Perform studies to identify motor neuron conduction block; presence of block suggests MMCB rather than ALS.
- Genetic Testing: If family history is positive or C9orf72/SOD1 are suspected, perform a panel for ALS and FTD genes.
- Neuropsychological Testing: Assess for cognitive impairment (common in ~15% of cases; higher in C9orf72 mutations).
MANAGEMENT & TREATMENT¶
- Pharmacologic Therapy: ◦ Riluzole: Dose: 100 mg/d. Effect: Modestly lengthens survival. ◦ Edaravone: Use to reduce the trajectory of worsening on disability scales. ◦ Tofersen: Indicated for SOD1-mediated ALS; administered via intrathecal delivery to suppress mutant SOD1 expression.
- Supportive Care: ◦ Respiratory Support: Management of respiratory failure (primary cause of death). ◦ Rehabilitative Aids: Implementation of assistive devices and physical therapy.
- Monitoring: ◦ Monitor for progression of bulbar symptoms and respiratory decline. ◦ Assess for development of pseudobulbar affect or cognitive changes.
PROGNOSIS & COMPLICATIONS¶
• Survival: Median 3–5 years; death usually from respiratory failure. • Complications: ◦ Respiratory paralysis. ◦ Dysphagia (difficulty swallowing) and aspiration risk. ◦ Pseudobulbar affect. ◦ Cognitive decline/Frontotemporal Dementia (especially in C9orf72 cases).
SPECIAL POPULATIONS¶
• Familial Cases: Higher likelihood of concurrent FTD; specific genetic targets (SOD1, C9orf72). ◦ Pediatric/Juvenile: Mutations in KIF5A or ALSIN may cause early-onset motor neuron disease. ◦ Traumatic Injury: Chronic traumatic encephalopathy can present with ALS-like features.
KEY PEARLS & HIGH-YIELD POINTS¶
• The "Rule of Two": ALS requires both UMN and LMN involvement; if only one is present, look for mimics. ◦ MMCB: If conduction block is present, it is likely MMCB (treatable with IVIG/chemotherapy). ◦ C9orf72: The most common genetic cause of FALS (~45-50%). ◦ Preservation: Sensory, bowel, and bladder functions are almost always preserved. ◦ Tofersen: Specifically for SOD1 mutations. ◦ Lead/Thyroid: Always rule out these treatable causes in patients with motor neuron symptoms.
Reference Tables¶
TABLE 448-2 Sporadic Motor Neuron Diseases CHRONIC Upper and lower motor neuron Predominantly upper motor neuron…¶
Harrison's 22e, p.3520
| DIAGNOSTIC CATEGORY | INVESTIGATION |
|---|---|
| Structural lesions Parasagittal or foramen magnum tumors Cervical spondylosis Chiari malformation of syrinx Spinal cord arteriovenous malformation |
MRI scan of head (including foramen magnum and cervical spine) |
TABLE 448-2 Sporadic Motor Neuron Diseases
| CHRONIC | ENTITY |
|---|---|
| Upper and lower motor neuron | Amyotrophic lateral sclerosis |
| Predominantly lower motor neuron | Multifocal motor neuropathy with conduction block |
| Motor neuropathy with paraproteinemia or cancer |
|
| Motor predominant peripheral neuropathies |
|
| Other | |
| Intoxications, physical agents Toxins—lead, aluminum, others Drugs—strychnine, phenytoin Electric short, x-irradiation |
24-h urine for heavy metals Serum lead level |
Table 448-1) Acute Poliomyelitis Herpes zoster Coxsackie virus West Nile virus¶
Harrison's 22e, p.3520
| Acute | |
|---|---|
| Poliomyelitis | |
| Herpes zoster | |
| Coxsackie virus | |
| West Nile virus | |
| Metabolic Hypoglycemia Hyperparathyroidism Hyperthyroidism D eficiency of folate, vitamin B , 12 vitamin E Malabsorption Deficiency of copper, zinc Mitochondrial dysfunction |
Fasting blood sugara Routine chemistries including calciuma PTH Thyroid functiona Vitamin B , vitamin E, folatea 12 Serum zinc, coppera 24-h stool fat, carotene, prothrombin time Fasting lactate, pyruvate, ammonia Consider mtDNA |
| Hyperglycinuria | Urine and serum amino acids CSF amino acids |
TABLE 448-3 Genetic Motor Neuron Diseases DISEASE I. Selected Upper and Lower Motor Neurons (Familial ALS) +…¶
Harrison's 22e, p.3522
| DISEASE | GENE SYMBOL |
GENE NAME | INHERITANCE | U.S. FREQUENCY % FALS |
USUAL ONSET | PROTEIN FUNCTION | UNUSUAL FEATURES |
|---|---|---|---|---|---|---|---|
| I. Selected Upper and Lower Motor Neurons (Familial ALS) + Frontotemporal Dementia (FTD) | |||||||
| C9ORF72 | Chromosome 9 open reading frame 72 |
AD | 45% (6–10% SALS) | Adult | Regulates vesicle trafficking |
||
| ALS | SOD1 | Cu/Zn superoxide dismutase 1 |
AD | 20% (2% SALS) | Adult | Protein antioxidant | |
| TARDBP | TAR DNA binding protein |
AD | 5% | Adult | DNA, RNA binding | ||
| ALS/ALS-FTD | FUS/TLS | Fused in sarcoma/ translocated in liposarcoma |
AD | 5% | Adult | DNA, RNA binding | |
| CCNF | E3 ubiquitin ligase cyclin F |
AD | 2% | Adult | Mediates ubiquitination |
||
| ALS | NEK1 | NMA-related kinase | AR | 2% | Adult | Microtubules, nuclear transport |
|
| TBK1 | Tank binding kinase 1 | AD | 2% | Adult | Regulates autophagy, inflammation |
||
| ALS | KIF5A | Kinesin family member 5A |
AD | 1–2% | Early adult | Microtubule motor | CMT |
| PFN1 | Profilin 1 | AD | ~1% | Adult | Involved in actin polymerization |
||
| ALS/ALS-FTD | OPTN | Optineurin | AD/AR | ~1% | Adult | Attenuates NF-κB | |
| SPG11 | Spastic paraplegia 11 | AR | ~1% | Adult | Vesicle trafficking | ||
| ALS | SETX | Senataxin | AD | ~1% | Late juvenile | DNA helicase | Late childhood onset |
| VCP | Valosin-containing protein |
AD | ~ 1% | Adult | ATPase | ||
| ALS-FTD | UBQLN2 | Ubiquilin 2 | XR | <1% | Adult or juvenile |
Protein degradation | |
| CHMP2B | Chromatin modifying protein 2B |
AD | <1% | Adult | Chromatin binding protein |
||
| ALS-FTD | MAPT | Microtubule Associated Protein Tau |
AD | <1% | Adult | Cytoskeletal protein | Usually causes only FTD |
| ALS2 | Alsin | AR | <1% | Juvenile | GEF signaling | ||
| ALS-FTD | CHMP2B | Chromatin modifying protein 2B |
AD | <1% | Adult | Chromatin binding protein |
|
| Spinal muscular atrophies |
SMN | Survival motor neuron | AR | 1/10,000 live births | Infancy | RNA metabolism | |
| HEXB | Hexosaminidase B | AR | Childhood | Ganglioside recycling | |||
| GM2A | GM2-activator protein | AR | Childhood | Ganglioside recycling | |||
| HEXA | Hexosaminidase A | AR | Childhood | Ganglioside recycling | |||
| X-linked spinobulbar muscular atrophy |
AR | Androgen receptor | XR | Adult | Nuclear signaling | ||
| SPG3A | ATL1 | Atlastin | AD | 10% AD FSP | Childhood | GTPase—vesicle recycling |
|
| SPAST | Spastin | AD | 50–60% AD FSP | Early adulthood | ATPase family— microtubule associate |
||
| SPG10 | KIF5A | Kinesin heavy chain isoform 5A |
AD | 10% AD FSP | Second–third decade |
Motor-associated protein |
± Peripheral neuropathy, retardation |
| REEP1 | Receptor Expression Enhancing Protein 1 |
AD | 10% AD FSP | Early | Mitochondrial protein | ||
| SPG5 | CYP7B1 | Cytochrome P450 | AR | 5–10% AR FSP | Variable | Degrades endogenous substances |
Sensory loss |
| SPG7 | Paraplegin | AR | 5–10% AR FSP | Variable | Mitochondrial protein |