Amyotrophic Lateral Sclerosis (ALS)
Key Clinical Features of ALS
The average age of onset is ~ 55 years old (but it can present at a wide range of ages) and that the average life expectancy from the time of diagnosis is ~ 3 years.
Diagnosis requires clinical evidence of UMN & LMN signs plus EMG evidence of acute and chronic denervation in multiple myotomes (muscle groups innervated by a single spinal nerve) in 3 regions (cervical, thoracic, lumbosacral, or cranial).
UMN Disease
- In upper motor neuron disease, there is spastic muscle tone, the reflexes are hyperactive (possibly with clonus), and there are pathologic reflexes (eg the Babinski sign) are present.
LMN Disease
- In lower motor neuron disease, there is flaccid muscle tone, the reflexes are hypoactive (or absent), and pathologic reflexes are absent.
Clinical Features of ALS
- The dysarthric pattern of speech in ALS is one of its most recognizable symptoms.
- There is characteristic preservation of extraocular muscle strength, which helps distinguish ALS from myasthenia gravis wherein asymmetric ptosis is the most common presenting feature.
- Focal asymmetric weakness (we show wrist drop, foot drop, and thigh wasting).
- Unlike myasthenia gravis and the inflammatory myopathies, ALS typically presents with an asymmetric, focal pattern of weakness and only later becomes confluent.
- Note that it can present in a myriad of different ways, including isolated bulbar dysfunction or isolated limb dysfunction. Imagine that it can present with degeneration of pretty much any pool of motor neurons and thus it can manifest in a variety of ways. Those presenting patterns are beyond the scope of this tutorial but include:
- Respiratory failure from diaphragm denervation, which is the leading cause of death in ALS.
Histopathology of ALS
Cytoplasmic inclusions are the key histopathological finding in ALS
- Bunina bodies: eosinophilic cytoplasmic inclusions; they are filled with a ubiquitin-negative, amorphous, electron-dense material.
- Although historically, Bunina bodies are the key pathologic marker in ALS, ubiquitin aggregates with TDP-43 positivity have since been found to be the most commonly identified abnormal cytoplasmic inclusions.
- TDP-43 normally localizes to the nucleus but in ALS it aggregates in the cytoplasm (just like in frontotemporal dementia, which helps link the disorders). Note that many other protein components to ubiquitin have been identified.
- It is believed that the pathological changes in ALS are, at least in part, secondary to aggregation of misfolded proteins, which disrupt normal cell functioning; impaired protein degradation; impaired cellular transport; and RNA toxicity.
- Co-occuring ALS with frontotemporal dementia can occur (TDP-43 positivity is a shared feature). In this setting, dementia may begin in tandem with weakness or precede it.
ALS Genetics
- ~ 10% of ALS is familial ALS.
- SOD1 gene mutation is found in is found in ~ 10% of familial ALS but only ~ 1.5% of sporadic ALS.
- TDP-43 + inclusions are NOT found in this form of ALS, thus it doesn't represent the classic phenotype.
- To date, the most impactful gene mutation to be discovered is C9orf72, which is found in ~ 40% of familial ALS, ~ 5-10% of sporadic ALS, and is the major cause of frontotemporal dementia.
Laboratory Work-up for ALS Differential Dx
The following labs are commonly performed to look for other key causes of weakness:
- Metabolic panel to look for electrolyte disturbance.
- Creatine kinase to look for myopathy.
- B12 and copper to look for subacute combined degenerative myelopathy.
- GM-1 antibody to look for multifocal motor neuropathy (which we address in part 2).
- SPEP/Immunofixation panel to look for monoclonal gammopathy.
Treatment
Disease-Modifying Treatments
No curative treatment exists for ALS. The following are considered life prolonging (disease-modifying) agents.
Riluzole
- Riluzole is believed to modify disease progression through a variety of mechanisms including reduction of glutamate excitotoxicity and release, as well as actions on NMDA and voltage-gated sodium channels.
- Riluzole provides a ~ 2 to 3 month survival benefit (according to a 2012 Cochrane Review) but certain patient populations may experience significantly longer benefit.
- Riluzole dosing is given at 50 mg PO BID. Key side effects include GI, especially liver dysfunction, and rarely neutropenia.
Edaravone
- Edaravone is a free-radical scavenger that is used to reduce oxidative stress, an important pathophysiological mechanism in ALS.
- Its efficacy is not well established but it likely, at least marginally, slows disease progression.
- Edaravone has both oral and IV formulations. Key side effects include injection-site reactions, ataxia, headache, and allergic reactions especially in asthmatics.
Tofersen (for SOD1 gene mutation ALS)
- Tofersen is used to inhibit SOD1 through gene-silencing mechanisms, thus, it is used exclusively in SOD1 gene mutation ALS patients.
- It's ultimate benefit remains to be fully determined but refer to this 2022 New England Journal of Medicine article for details "Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS".
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