Amyotrophic Lateral Sclerosis

Etiology

A single and precise etiology governing ALS is lacking. The possible mechanisms described in the literature are genetic mutations, oxidative stress, excitotoxicity, mitochondrial and proteasomal dysfunctions, altered synaptic function, disturbed axonal transport, and neuroinflammation.[3][4] The risk variables include sports with a high incidence of concussions, military jobs, smoking, exposure to heavy metals (lead, manganese), pesticides, neurotoxins (cyanobacteria), and electromagnetic fields.[1][5] It appears that ALS develops as a result of the interaction between both genetic and environmental factors.

Over 120 genes have been implicated in ALS.[1][6] A prevailing thought is that the accumulation of abnormal proteins due to aberrant RNA processing is involved in the development of ALS. Variants of TDP-43 and FUS, two genes for RNA binding proteins, are involved in familial ALS.[7] Patients with variant forms of these genes will have TDP-43 and FUS proteins found primarily in the cytoplasm instead of the nucleus, causing neurodegeneration. In addition, a non-coding stretch of hexanucleotide repeats (to hundreds or thousands) of C9ORF72, which plays a pivotal role in membrane trafficking and autophagy, is the most commonly mutated gene associated with ALS (45% in familial and 7% of sporadic ALS compared to 20% for SOD1).[1][7] Mutations to this gene are also involved in the development of frontotemporal dementia (FTD). Patients with this genetic mutation may develop only ALS, only FTD, or a combination of both. Approximately 50% of people with C9ORF72 expansions develop ALS by age 60 and nearly 100% by age 80.[5]

Superoxide dismutase 1 (SOD1), responsible for converting superoxide radicals to oxygen and hydrogen peroxide, was the first gene discovered in 1993. This prompted the belief that altered protein synthesis is the primary mechanism involved with SOD1 variant ALS (20% of familial cases and 1% of sporadic cases). Cytoskeletal variables such as dynactin 1 (controls retrograde axonal transport), PFN1 (governs the conversion of globular to filamentous actin and nerve extension), and Tubulin 4A (regulates microtubules) are also implicated.[1] The functional deficits at the neuromuscular junction (NMJ) have been observed at least 6 weeks prior to the onset of motor symptoms.[8] SOD1 and profilin 1 (PFN1) are the most commonly applied models for animal studies.[1] The possible role of the brain-gut-microbiota axis in pathogenesis has also been described.[9]

Epidemiology

Of the two forms of amyotrophic lateral sclerosis, 90% to 95% of cases are sporadic (showing a male preponderance of 2:1), with the remainder being familial (male: female ratio of 1:1).[7] The majority of patients with sporadic ALS are found to have an underlying genetic susceptibility (the rest owing to environmental influences).[10] 

The lifetime risk of developing ALS is 1:350 for men and 1:400 for women.[5][7] The mean age of involvement is 64.[1][11] This risk is maximum at approximately 75 years.[7] The prevalence of ALS in 22 European countries was 121,028 cases in 2020, with 800,000 cases reported in the US.[1] 380,000 cases worldwide are predicted by 2040.[3] The global incidence is 1 to 2.6 per 100,000 with a prevalence of 4 to 5 per 100,000.[3][5][7] The incidence ranges from 0.26 per 100,000 persons per year in Ecuador to 23.46 per 100,000 per year in Japan. The point prevalence also differs from 1.57 per 100,000 in Iran to 11.80 per 100,000 in the United States.[12] 

Pathophysiology

The pathological hallmarks of ALS are the degeneration of the pyramidal Betz cells in the motor cortex, anterior horn cells of the spinal cord (due to retrograde axonal loss), and lower cranial motor nuclei of the brainstem. Gliosis replaces the lost neurons. As a result, the spinal cord atrophies along with the affected muscles. [1][13] A variety of intracellular inclusions are common in degenerating neurons. Bunina bodies are eosinophilic inclusions unique to ALS.[14] The accumulation of TDP-43 is present in most cases of sporadic ALS, FTD, ALS-FTD, and some cases of familial ALS. 

The interplay of epigenetics (ie, a modification of gene expression rather than a modification of the genetic code itself), a trigger factor (risk variables described above), a propagating channel (oxidative stress, excitotoxicity, defective RNA processing, intraneuronal protein aggregates, mitochondrial dysfunction, neuroinflammation, or protein misfolding) and final clinical manifestations have also been advocated.[7]

Histopathology

The pathologic hallmarks of the condition were first described by Charcot. There is a loss of motor neurons amid neuroinflammation.[5] Bunina bodies, cytoplasmic transactive response DNA-binding protein 43 (TDP-43) inclusions, and intra-nuclear RNA deposits (C9ORF72 ALS) are also diagnostic.[4]

History and Physical

The clinical presentation of ALS is heterogeneous.[1] The hallmark feature is upper and lower motor neuron signs and symptoms coexist. Upper motor neuron (UMN) findings are hyperreflexia, poor dexterity, incoordination, and spasticity. Dysarthria and dysphagia are common bulbar upper motor neuron findings. Lower motor neuron (LMN) findings are muscle atrophy and fasciculations.[1] Weakness, a hallmark feature, can be attributed to upper or lower motor neurons.

The initial presentation determines the pattern of symptom progression and provides prognostic significance. Most patients present with asymmetric LMN symptoms isolated to the arm or leg.[15] Common initial clinical findings are hand weakness, shoulder girdle weakness, and foot drop. Bulbar onset ALS accounts for 25% of patients. The most common bulbar symptoms are dysarthria and dysphagia. Others are hypernasal speech, laryngospasm, involuntary cheek or tongue biting, and sialorrhea followed by limb involvement in later stages.[1][15] Eye and sphincter muscles are spared until late in the disease.[1] A few patients present with respiratory muscle weakness or generalized weakness in combination with weakness in the bulbar muscles.[5][16] 

Many patients (30% to 50%) diagnosed with ALS will develop varying degrees of cognitive impairment, and 15 to 20% of cohorts develop frontotemporal dementia (Pick’s disease).[1] While not presenting with overt dementia, patients can experience changes related to executive function and fluency, as well as behavioral changes such as apathy and disinhibition. Pseudobulbar palsy (ie, inappropriate periods of crying, laughing, or yawning) is also observed due to the involvement of frontopontine motor neurons.[1] Autonomic symptoms (constipation), paresthesias, and pain (due to immobility and muscle cramps) may also occur. In the presence of these symptoms, the diagnosis is ALS-plus syndrome.[17] 

As discussed earlier, there is a spectrum of motor neuron diseases (ie, progressive muscular atrophy and primary lateral sclerosis). The involvement of upper and lower motor neurons currently defines each. Although debated, some experts believe progressive muscular atrophy (PMA) represents a form of ALS. The disease is progressive and initially exclusively involves the LMN. Many patients progress and develop clinical signs and symptoms of UMN disease, at which point the diagnosis becomes lower motor neuron-onset ALS. Interestingly, in patients who never show clinical evidence of UMN involvement, corticospinal tract involvement is detected at autopsy in more than 50% of patients with an antemortem diagnosis of PMA.[18] Primary lateral sclerosis (PLS) initially presents with exclusively UMN symptoms. Most will eventually develop LMN symptoms, and the diagnosis becomes upper motor neuron-dominant ALS.[19] These patients have a slower progression of symptoms, lack weight loss, and LMN signs and symptoms in the first four years of the disease. 

The clinical phenotypes of traditional ALS are typical spinal onset, bulbar onset, flail arm syndrome, flail leg phenotype, hemiplegic, pseudo-polyneuritic phenotype, mixed, and thoracic/respiratory onset variants.[5][20]  Flail arm syndrome ( or brachial amyotrophic diplegia), is characterized by LMN weakness and wasting. It usually causes symmetric proximal weakness in the upper limbs.[21] Another variant is flail leg syndrome (pseudo-polyneuritic variant), also characterized by weakness and wasting, but of the lower extremities and with distal onset. Patients with flail arm and leg syndrome have a slower rate of progression to the involvement of other body segments and respiratory muscle weakness.[22] These variants are difficult to differentiate from typical ALS as the diagnostic criteria are primarily the length of time symptoms remain localized to the initial extremity regions. 

Progression of ALS is usually linear, without episodes of remissions or exacerbations. While the rate of progression varies between individuals, the pattern of progression is relatively predictable. The most common pattern in patients is unilateral limb onset (again, the predominant form), which progresses to include the contralateral limb, then the other ipsilateral extremity (ie, the leg if the initial weakness was in the arm), followed by the other contralateral extremity, before ultimately affecting the bulbar muscles.

Evaluation

Due to its variable presentation, lack of diagnostic markers, and similarity to various motor neuron diseases, ALS is primarily a clinical diagnosis. The revised El Escorial criteria were developed to properly place patients in clinical trials and provide diagnostic certainty. The revised El Escorial criteria were subsequently altered to incorporate relevant electrophysiological changes (equivalent to clinical LMN findings) and help improve diagnostic sensitivity.[5][23] Specifically, the Awaji criteria state that diagnosing ALS requires clinical, electrophysical, or neuropathological evidence of combined lower and upper motor neuron degeneration with progression and excludes treatable clinical mimics.[24] 

All patients with motor neuron disease should undergo nerve conduction studies and electromyography (EMG). They are helpful in further supporting the diagnosis if the clinical picture is unclear. EMG contributes to the diagnosis in up to 90% of cases.[16]. Expected electromyography (EMG) findings are acute denervation (fibrillation and positive sharp waves), chronic denervation (long-duration, complex motor unit action potentials [MUAP]), and chronic reinnervation (large amplitude MUAP).[1][25] Sensory action potentials will be normal. Motor nerve action potential amplitudes may be low before weakness is clinically evident.[26] EMG criteria for diagnosing ALS are acute or chronic denervation in at least three spinal levels (bulbar, cervical, thoracic, or lumbosacral). If three spinal levels are not abnormal, acute or chronic denervation must be evident in three extremities involving at least two muscles supplied by two different nerve roots in each extremity. There should be no features of demyelination (prolonged distal latencies >30%, conduction block, or reduced velocity <70%).[5] 

The role of radiology in evaluating ALS is primarily to exclude other potential causes of the patient's symptoms. MRI is the imaging study of choice. MRI will typically be normal with ALS. Occasionally, decreased signal intensity within the motor cortex on T2-weighted images (T2WI) and well-defined lesions of increased signal intensity can be visible within the corticospinal tracts on T2WI. The "motor band sign" is a decreased signal visible on susceptibility-weighted imaging across the precentral gyrus caused by the accumulation of iron within the precentral gyrus.[27][28] Findings indicative of upper motor neuronal disease have been noted utilizing experimental advanced MRI techniques such as spectroscopy and diffusion tensor imaging (DTI).[28][29] Fiber density and cross-section provided the greatest sensitivity to longitudinal change.[30] MR spectroscopy with a reduced N-acetyl aspartate-inositol ratio is very specific.[3][31][32] T2/FLAIR hyperintensities along the corticospinal tract and internal capsule are also affirmative. 

To monitor disease progression, the King's staging system was developed.

 The grading of the King's system includes:

• Stage 1-Symptom onset with involvement of the first region
• Stage 2A-Diagnosis
• Stage 2B-Involvement of the second region
• Stage 3-Involvement of the third region
• Stage 4A-Need for gastrostomy 
• Stage 4B-Need for noninvasive ventilation
• Stage 5-Death[5][20]

The majority of affected patients are diagnosed within King's Stage 2, with only 16% initially assessed by a neurologist.[16] Healthcare providers can use the 'thinkALS' and 'MND Red Flag' tools to help with earlier diagnosis.[16] PRECISION-ALS (a large European research initiative) was formed to ensure precision medicine.[33]

Due to emerging genotype-specific therapies in clinical trials, genetic testing is encouraged upon diagnosis, particularly for the SOD1 and C9ORF72 genotypes. Genetic testing can be used as a screening tool for patients with a family history of autosomal dominant disease and prognostic implications. This can also help to elucidate the degree of penetrance. ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways.[34]

Treatment / Management

The treatment of ALS is multidisciplinary and involves physical, occupational, and speech therapists, home ventilation therapy, nutrition support, psychotherapy, training for caregivers, cognitive screening, and end-of-life care.[3][20] Symptomatic management is the mainstay of treatment.[35](A1)

Riluzole, Edaravone, and sodium phenylbutyrate are the only approved medications to treat ALS but provide limited survival benefits.[1][3] Riluzole, 50mg bid, is recommended for all patients with ALS and is thought to reduce glutamate-induced excitotoxicity. Riluzole is the only medication that improves overall survival (74% vs. 58% in the placebo group at 12 months) and slows the progression of symptoms (ie, survival without tracheostomy (57% vs. 50% at 18 months). Riluzole is most effective in patients who have been symptomatic for less than 5 years, have a vital capacity (VC) >60% of the predicted value, and do not require a tracheostomy.[36] It is important to note that the elimination of riluzole will be affected by CYP1A2 inhibitors like caffeine and theophylline (decrease the rate of elimination of riluzole). Transaminase elevation occurs in approximately 50% of patients. Monitor transaminases monthly for the first three months and every three months after. (B2)

Edaravone is a free radical scavenger that is thought to reduce oxidative stress and slow functional progression. Edaravone provides the most benefit in patients with early ALS (ie, less than two years of symptoms, living independently, VC >80%, and scores of 2 or more in all items of ALSFRS-R) with probable or definite ALS (revised El Escorial criteria). One study showed approximately 33% slower functional decline in patients at 24 weeks follow-up.[37] Edaravone treatment is expensive ($146,000 annually). Edaravone should be used with caution in patients with asthma. It contains sodium bisulfite, which may cause asthmatic reactions in up to 5% of patients. (A1)

Sodium phenylbutyrate is a histone deacetylase inhibitor that decreases the stress response in the endoplasmic reticulum. Combined with taurursodiol (which increases the threshold for cellular apoptosis), it decreases neuronal destruction. The result is a slower decline in function. Sodium phenylbutyrate-taurursodiol is administered intrathecally and may result in myelitis, radiculitis, aseptic meningitis, and elevated intracranial pressure.

Patients with ALS will suffer from chronic respiratory failure due to weakness of the diaphragmatic and intercostal muscles. Pulmonary function tests are done every three months. As this weakness is progressive, an early, careful discussion regarding respiratory management and future options such as tracheostomy, chronic ventilatory support, and noninvasive ventilation (NIV) is warranted. The discussion should evolve with the progression of symptoms and patient readiness. NIV will be helpful when the vital capacity (VC) is less than 50%, sniff nasal inspiratory pressure (SNIP) < 40 cm H2O, pCO2 > 45mmHg, significant desaturations are noted on overnight oximetry, or when evidence of respiratory weakness is present.[20] The use of NIV prolongs survival.[5] Invasive ventilation is considered when NIV is no longer tolerated, or when the patient continues to experience hypoxia or hypercarbia despite NIV. Survival after beginning invasive ventilation is approximately 30 months. Patients should understand that they can discontinue therapy at any time during the treatment process. Immunization with the annual influenza and pneumococcal vaccines is important. (A1)

Initially managed with diet modifications, progressive weakening of the muscles of mastication and swallowing results in dysphagia. Weight loss (particularly within the first two years after diagnosis) is associated with a poorer prognosis. Emphasis should be placed on the intake of calorically dense foods and supplemental nutritional beverages.[38] Enteral tube feeding is indicated when weight loss exceeds 10%, BMI is less than 18.5 kg/m2, swallowing impairments are observed during instrumental tests, or the VC is <50%.[20] PEG is superior in terms of quality-of-life measures. If the patient elects to have a G-tube placed, this should be completed before the VC becomes <50% of the predicted value to avoid increased morbidity associated with the procedure itself.[36] Tertiary ALS centers increase six-month survival as well as reduce time to noninvasive ventilation (NIV) and Gastrostomy.[3] (A1)

As the disease progresses, there will be increased dysarthria and the inability to communicate. Speech therapy provides limited benefit, and appropriate alternative communication methods (writing, alphabet boards, and electronic assistive communication devices) are needed.[39](B2)

Frequent and painful muscle spasms are common. Mexiletine (a sodium channel-blocking antiarrhythmic drug) is effective at a 150 mg BID dose.[40][41] Other options include levetiracetam, gabapentin, baclofen, and tizanidine.[42] When oral therapy is impractical, botulinum toxin injections into the spastic muscles can be helpful. As weakness and functional decline inevitably progress, patients use assistive devices (canes, orthoses, crutches, and eventually wheelchairs), removable headrests in those with neck weakness, specialized utensils and holders, and eventually a pressure-relieving mattress with frequent repositioning to prevent pressure ulcers.[43] Sialorrhea is very common and can be treated with atropine, hyoscyamine, amitriptyline, glycopyrrolate, botulinum toxin injections into salivary glands, and even low-dose radiation therapy in those with refractory symptoms.[35][44] (A1)

AVP-923 (dextromethorphan-quinidine 20mg/10mg) has proven effective in patients with pseudobulbar affect.[45] Less rigorous evidence has supported the use of amitriptyline and fluvoxamine in smaller trials. Pain is treated based on its underlying cause. Non-steroidal anti-inflammatory medications, paracetamol, intra-articular steroids, or lidocaine injections are recommended for nociceptive pain, whereas gabapentin, pregabalin, tricyclic antidepressants, and morphine are advised for neuropathic pain. Mexiletine, levetiracetam, and quinine sulfate help patients with cramps. Assistive devices such as special mattresses, pillows, and wheelchairs may help to prevent pain. Ultimately, many patients require nonopioid analgesics and anti-inflammatory medications, and when these fail, opioids become the mainstay of pain treatment.[46] (A1)

Depression is common, and treatment improves the quality of life. Amitriptyline is commonly used as it can also treat other symptoms such as insomnia, sialorrhea, and pseudobulbar affect. Selective serotonin reuptake inhibitors are another alternative if the TCAs are not tolerated. The issue of end-of-life care and advanced directives should be broached soon after diagnosis. Treating dyspnea and anxiety is essential. In addition to NIV, relaxation techniques, psychosocial support, morphine, and benzodiazepines are helpful. Insomnia should be first addressed by treating the underlying cause (ie, dyspnea, pain, or anxiety). Tricyclic antidepressants and benzodiazepines are medication options.[20] Hospice and palliative care providers can provide many resources that are not available or as readily available in the home and can increase the likelihood of a peaceful death.[47] Ongoing trials focus on nanoparticles' role, viral vectors, monoclonal-antibody, and stem cells.[1][3] Artificial intelligence (AI) and machine learning may prove to be a prodigy in management.[48](A1)

Differential Diagnosis

The LMN Mimics

• Benign fasciculations
• Inclusion body myopathy
• Multifocal motor neuropathy
• Monomelic amyotrophy
• Neuralgic myopathy
• Hirayama disease
• Spinobobulbar muscular atrophy 
• Distal spinal atrophy syndrome (Charcot-Marie-Tooth disease)

The UMN Mimics

• Hereditary spastic paraplegia
• Adrenomyeloneuropathy
• Late-onset Tay-Sachs disease
• Polyglucosan body disease
• HIV myelopathy
• Multiple sclerosis 
• Myasthenia gravis
• Nutritional myeloneuropathies
• Post-polio syndrome

A Mixed Pattern

• Cervical radiculomyelopathy
• Hyperthyroidism[5][49][50][51][52]

Prognosis

There is no cure for ALS.[5][7] The median survival is 3 to 5 years. Approximately 30% of patients survive 5 years and 10% ten years. Riluzole provides a survival benefit averaging 3 months, with edaravone showing a 33% reduction in the decline of the ALS Functional Rating Scale–Revised (ALSFRS-R) at 6 months. 

Factors governing improved survival include mild obesity at the time of diagnosis, younger age at onset, higher ALS Functional Rating Scale score, better forced vital capacity (FVC), and limb (rather than bulbar) symptoms on presentation.[53][54] Patients with the flail-arm syndrome phenotype also survive longer.[1] SOD1 mutations show predominantly lower limb onset, and TARDP mutations have upper limb onset. Lower expression of EPHA4 connotes a more prolonged survival. Increased age at onset, a short delay from symptom onset to diagnosis, and the earlier use of NIV are all prognostic indicators of a more aggressive progression.[2] Accelerated progression is also observed in the A4V mutation of SOD1 and P525L mutation of FUS/TLS, showing a fulminant childhood pattern.[1] FUS mutations have an earlier age of onset and shorter lifespan.[7]

Complications

There are numerous complications associated with amyotrophic lateral sclerosis, including respiratory decline with eventual need for ventilatory support, dysphagia, dysarthria, malnutrition, muscle spasms, spasticity, fatigue, functional decline due to muscular weakness, sialorrhea, thick mucus secretions, and pseudobulbar affect. Aspiration pneumonia and respiratory insufficiency are the most common causes of death.[7] In addition, some complications may arise due to the medications meant to manage disease symptoms. Mexiletine can cause gastrointestinal upset and arrhythmias. Riluzole can lead to transaminitis and asthenia, whereas edaravone can cause gait disturbance and headache.