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Also known as Lou Gehrig's disease, it is a progressive nervous system disease that damages nerve cells in the brain and spinal cord, resulting in loss of muscle control. The exact cause is unknown, there is no cure, and the disease is fatal.

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Overview

Amyotrophic lateral sclerosis (a-my-o-TROE-fik LAT-ur-ul skluh-ROE-sis), known as ALS, is a nervous system disease that affects nerve cells in the brain and spinal cord. ALS causes loss of muscle control. The disease gets worse over time.

ALS is often called Lou Gehrig's disease after the baseball player who was diagnosed with it. The exact cause of the disease is still not known. A small number of cases are inherited.

ALS often begins with muscle twitching and weakness in an arm or leg, trouble swallowing or slurred speech. Eventually ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for this fatal disease.

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Symptoms

Symptoms of ALS vary from person to person. Symptoms depend on which nerve cells are affected. ALS generally begins with muscle weakness that spreads and gets worse over time. Symptoms might include:

Trouble walking or doing usual daily activities.

Tripping and falling.

Weakness in the legs, feet or ankles.

Hand weakness or clumsiness.

Slurred speech or trouble swallowing.

Weakness associated with muscle cramps and twitching in the arms, shoulders and tongue.

Untimely crying, laughing or yawning.

Thinking or behavioral changes.

ALS often starts in the hands, feet, arms or legs. Then it spreads to other parts of the body. Muscles get weaker as more nerve cells die. This eventually affects chewing, swallowing, speaking and breathing.

There's generally no pain in the early stages of ALS. Pain also is not common in the later stages. ALS doesn't usually affect bladder control. It also usually doesn't affect the senses, including the ability to taste, smell, touch and hear.

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Causes

ALS affects the nerve cells that control voluntary muscle movements such as walking and talking. These nerve cells are called motor neurons. There are two groups of motor neurons. The first group extends from the brain to the spinal cord to muscles throughout the body. They're referred to as upper motor neurons. The second group extends from the spinal cord to muscles throughout the body. They're referred to as lower motor neurons.

ALS causes both groups of motor neurons to gradually deteriorate and then die. When motor neurons are damaged, they stop sending messages to the muscles. As a result, the muscles can't function.

For about 10% of people with ALS, a genetic cause can be identified. For the rest, the cause is not known.

Researchers continue to study possible causes of ALS. Most theories center on a complex interaction between genes and factors in the environment.

Risk factors

Established risk factors for ALS include:

Genetics. For about 10% of people with ALS, a risk gene was passed down from a family member. This is called hereditary ALS. In most people with hereditary ALS, their children have a 50% chance of inheriting the gene.

Age. Risk increases with age up to age 75. ALS is most common between the ages of 60 and the mid-80s.

Sex. Before the age of 65, slightly more men than women develop ALS. This sex difference disappears after age 70.

Environmental factors, such as the following, have been associated with an increased risk of ALS.

Smoking. Evidence supports that smoking is an environmental risk factor for ALS. Women who smoke seem to be at even higher risk, particularly after menopause.

Environmental toxin exposure. Some evidence suggests that exposure to lead or other substances in the workplace or at home might be linked to ALS. Much study has been done, but no one agent or chemical has been consistently associated with ALS.

Military service. Studies indicate that people who have served in the military are at higher risk of ALS. It's not clear what about military service might trigger ALS. It might include exposure to certain metals or chemicals, traumatic injuries, viral infections, or intense exertion.

Complications

As the disease progresses, ALS causes complications, such as:

Breathing problems

Over time, ALS leads to weakness of the muscles used to breathe. People with ALS might need a device such as a mask ventilator to help them breathe at night. The device is similar to what someone with sleep apnea might wear. This type of device supports the person's breathing through a mask worn over the nose, the mouth or both.

Some people with advanced ALS choose to have a tracheostomy. This is a surgically created hole at the front of the neck leading to the windpipe. A ventilator may work better on a tracheostomy than on a mask.

The most common cause of death for people with ALS is breathing failure. Half of people with ALS die within 14 to 18 months of diagnosis. However, some people with ALS live 10 years or longer.

Speaking problems

Most people with ALS develop weakness of the muscles used to form speech. This usually starts with slower speech and occasional slurring of words. It then becomes harder to speak clearly. This can progress to the point that others can't understand the person's speech. Other forms of communication and technology are used to communicate.

Eating problems

People with ALS can develop weakness of the muscles involved with swallowing. This can lead to malnutrition and dehydration. They are also at higher risk of getting food, liquids or saliva into the lungs, which can cause pneumonia. A feeding tube can reduce these risks and ensure proper hydration and nutrition.

Dementia

Some people with ALS have problems with language and decision-making. Some are eventually diagnosed with a form of dementia called frontotemporal dementia.

Show references

1. Just what is ALS? ALS Association. https://www.als.org/understanding-als/what-is-als. Accessed Feb. 16, 2023.

2. Ferri FF. Amyotrophic lateral sclerosis. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Feb. 16, 2023.

3. Elman LB, et al. Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease. https://www.uptodate.com/contents/search. Accessed Feb. 16, 2023.

4. Preston DC, et al. Amyotrophic lateral sclerosis and its variants. In: Electromyography and Neuromuscular Disorders. 4th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Feb. 16, 2023.

5. Elman LB, et al. Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease. https://www.uptodate.com/contents/search. Accessed Feb. 16, 2023.

6. Goldman L, et al., eds. Amyotrophic lateral sclerosis and other motor neuron diseases. In: Goldman-Cecil Medicine. 26th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Feb. 16, 2023.

7. Amyotrophic lateral sclerosis (ALS) fact sheet. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet. Accessed Feb. 16, 2023.

8. Environmental factors. ALS Association. https://www.als.org/research/research-we-fund/scientific-focus-areas/environmental-factors. Accessed Feb. 16, 2023.

9. After the ALS diagnosis: Coping with the 'new normal.' ALS Association. http://www.alsa.org/als-care/resources/publications-videos/resource-guides/. Accessed Feb. 16, 2023.

10. Ami TR. Allscripts EPSi. Mayo Clinic. Dec. 22, 2022.

11. Dharmadasa T, et al. Genetic testing in motor neuron disease. Practical Neurology. 2022; doi:10.1136/practneurol-2021-002989.

12. Mehta P, et al. Incidence of amyotrophic lateral sclerosis in the United States, 2014-2016. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. 2022; doi:10.1080/21678421.2021.2023190.

13. Relyvrio (approval letter). New Drug Application 216660. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. Accessed Feb. 17, 2023.

14. Yamakawa M, et al. Demographics, clinical characteristics and prognostic factors of amyotrophic lateral sclerosis in Midwest. Muscle & Nerve. 2022; doi:10.1002/mus.27450.

15. Van Blitterswijk M, et al. How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: Can we learn from other noncoding repeat expansion disorders? Current Opinion in Neurology. 2012; doi:10.1097/WCO.0b013e32835a3efb.

16. ALS certified centers and clinics. ALS Association. https://www.als.org/local-support/certified-centers-clinics?search_api_fulltext=Mayo+Clinic. Accessed Dec. 8, 2022.

17. Barry RL, et al. Ultra-high field (7T) functional magnetic resonance imaging in amyotrophic lateral sclerosis: A pilot study. NeuroImage Clinical. 2021; doi:10.1016/j.nicl.2021.102648.

18. Dorst J, et al. Clinical studies in amyotrophic lateral sclerosis. Current Opinion in Neurology. 2022; doi:10.1097/WCO.0000000000001099.

19. Oskarsson BE (expert opinion). Mayo Clinic. Jan. 6, 2023.

20. Sun Y, et al. An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis. Expert Review of Neurotherapeutics. 2023; doi:10.1080/14737175.2023.2174018.

21. Sturmey E, et al. Blood biomarkers in ALS: Challenges, applications and novel frontiers. Acta Neurologica Scandinavica. 2022; doi:10.1111/ane.13698.

22. Soga T, et al. Long-term outcomes after surgery to prevent aspiration for patients with amyotrophic lateral sclerosis. BMC Neurology. 2022; doi:10.1186/s12883-022-02619-z.

23. Rutkove SB, et al. Differential diagnosis of peripheral nerve and muscle disease. https://www.uptodate.com/contents/search. Accessed March 9, 2023.

24. National Amyotrophic Lateral Sclerosis (ALS) Registry. Centers for Disease Control and Prevention. https://www.cdc.gov/als/GeneralPublic_AboutRegistry.html. Accessed March 9, 2023.

25. Johnson SA (expert opinion). Mayo Clinic. March 8, 2023.

26. Staff NP (expert opinion). Mayo Clinic. March 9, 2023.

27. Oskarsson BE (expert opinion). Mayo Clinic. Feb. 21, 2023.

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Amyotrophic lateral sclerosis (ALS) - Symptoms and causes

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This progressive nervous system disease, also known as Lou Gehrig's disease, destroys nerve cells.

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I can still remember seeing the first signs and symptoms of this disease from someone dear to my family. Watching the disease slowly progress and take her independence and regular self, was very hard to witness. It left me with many questions and genuine curiosity as to why this happens. This project will help me gain better understanding of ALS from a medical standpoint, as well as from the perspecive eof those living with it

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Book containing valuable information from etiology to complications of ALS

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Continuing Education Activity

Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig's disease," is a neurodegenerative disease of the motor neurons. This activity reviews the etiology and evaluation of amyotrophic lateral sclerosis (ALS). In addition, it outlines the treatments and interventions available. This activity highlights the role of the interprofessional healthcare team in evaluating and treating patients with this condition.

Objectives:

Summarize the etiology of ALS.

Outline the typical findings on the examination of a patient with ALS.

Describe the interventions available for patients with ALS.

Review the importance of collaboration and communication among the interprofessional team to enhance the coordination of care for patients affected by ALS.

Access free multiple choice questions on this topic.
Introduction

Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig disease," is a neurodegenerative disease of the motor neurons. No single etiology has been proven; rather, multiple pathways (both heritable and sporadic) have been shown to result in unmistakably similar disease entities. ALS necessarily affects both upper and lower motor neurons with variable patterns of onset, most commonly beginning with signs of lower motor neuron degeneration within proximal limbs. As it is a progressive disease, it will eventually lead to paralysis and, inevitably, death. There is no cure for ALS; however, multiple medications and interventions can reduce symptoms and prolong life, sometimes up to 10 or more years.

Etiology

Although many potential mechanisms have been proposed, a precise, single etiology of sporadic amyotrophic lateral sclerosis is yet unproven. These mechanisms include altered RNA processing leading to prion-like self-aggregation, superoxide dismutase type 1 SOD1 mutations leading to free radical toxicity, cascading inflammatory responses, and excessive concentrations of glutamate, among others.[1][2] The rarer entity of familial ALS has numerous genetic mechanisms, most frequently repeat expansion of the C9ORF72 gene and various mutations of the SOD1 gene.[3] Mutated SOD1 protein misfolds and forms aggregates, leading to cellular injury and eventually apoptosis. Both genetic aberrations are inherited in a mainly autosomal dominant pattern.[4] Ultimately, rather than a single unifying cause, ALS is an etiologically diverse clinical entity, which is the result of a multitude of separate potential preceding aberrations.[5]

Epidemiology

Of the two forms of amyotrophic lateral sclerosis, 90-95% of cases are sporadic, with the remainder being familial. Within the United States, the prevalence of the disease is estimated at 5.2 per 100,000.[6] Worldwide incidence is approximately 1.6 cases per 100,000 persons annually, with similar rates demonstrated within the United States.[7][8] For sporadic ALS, male-to-female incidence ratios ranging from 1.3 to 1.5 have been demonstrated. Increased incidence is also noted with increases in age, particularly after 40 years of age.[9] Globally, a higher incidence is associated with White ethnicity.[10][11] The only established risk factors for ALS are age and family history; however, a growing body of evidence suggests cigarette smoking may also be a risk factor.[12]

Pathophysiology

The pathology of amyotrophic lateral sclerosis is characterized by the degeneration and gliosis of axons within the anterior and lateral columns of the spinal cord. Motor neurons within the spinal cord anterior horns and Betz cells within the motor cortex are also lost.[13] Unique to amyotrophic lateral sclerosis, Bunina bodies are eosinophilic inclusions visible in affected motor cells in many cases.[14] Intracellular TDP-43 inclusions are present in most cases, providing a pathologic link between ALS and frontotemporal dementia (FTD), in which they are also found.[15]

History and Physical

The most distinctive feature of Amyotrophic lateral sclerosis is the coexistence of upper and lower motor neuron signs and symptoms. Upper motor neuron (UMN) findings include hyperreflexia and spasticity, lower motor neuron (LMN) findings include muscle atrophy and fasciculations. Weakness can be attributed to either UMN or LMN. There are different phenotypes that determine the pattern of the above-mentioned symptoms and signs, as well as having prognostic significance:

Limb onset ALS (LO) is the predominant type, presenting in 70% of patients.[16] LO ALS can be further classified as flail arm syndrome or brachial amyotrophic diplegia, which is characterized by LMN weakness and wasting. It usually starts proximally and often symmetrically, then progresses distally to a point where upper extremity function is severely impaired.[17] LO ALS can also be classified as flail leg syndrome or pseudopolyneuritic variant, which is also characterized by LMN weakness and wasting, but of the lower extremities and with distal onset. Patients have a slower rate of progression to the involvement of other body segments and respiratory muscle weakness.[18]

Bulbar onset ALS accounts for 25% of patients and is characterized by UMN and LMN involvement of the cranial nerves, usually manifesting as speech difficulties and dysphagia followed by limb involvement in later stages.[16]

Although debated, some experts believe progressive muscular atrophy (PMA) represents a form of ALS. The disease is progressive, initially exclusively involving the LMN. Many patients go on to develop clinical signs and symptoms of UMN disease, at which point it is called lower motor neuron-onset ALS. Interestingly, even in those patients who never show clinical evidence of UMN involvement, corticospinal tract involvement is detected at autopsy in up to 50% to 66% of patients with an antemortem diagnosis of PMA.[19]

Primary lateral sclerosis (PLS) is a disorder of initially exclusive UMN disease. These patients have slower progression, lacking weight loss, and LMN symptoms/signs in the first four years of the disease. Most will eventually develop them, however, and at this point is known as upper motor neuron-dominant ALS.[20] These patients have a better prognosis than typical patients with ALS but worse than patients with PLS.[21]

If there are any additional symptoms/signs besides LMN and UMN disease, such as dementia (mostly frontotemporal), extrapyramidal, autonomic dysfunction, ocular motility disturbance, and/or sensory loss, these patients are considered to have ALS-plus syndrome.[22]

FTD, in particular, has a significant coincidence with ALS, with approximately 15% of patients with ALS demonstrating criteria for FTD. Many patients (about 30% to 50%) diagnosed with ALS will go on to develop varying degrees of cognitive impairment. While not overt dementia, patients can experience changes related to executive function and fluency, as well as behavioral changes such as apathy and disinhibition.

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

Evaluation

A widely accepted set of clinical criteria for the reliable diagnosis of Amyotrophic lateral sclerosis is the revised El Escorial criteria. Most recently updated in 1998, the criteria involve both specific findings that must be present and others that must be absent. The diagnosis requires evidence of both upper and lower motor neuron degeneration, together with the progressive spread of symptoms or signs. Also, there can be no evidence (electrophysiological, pathological, or radiological) of other disease processes that may be causing the aforementioned signs and symptoms.[23] Examples of lower motor neuron signs include weakness, muscle atrophy, and fasciculation, while clonus and pathologic spread of reflexes are upper motor neuron signs.

Specifically, the revised El Escorial criteria state that the diagnosis of ALS requires the presence of:

Clinical, electrophysical, or neuropathologic evidence of lower motor neuron degeneration,

Clinical, electrophysical, or neuropathologic evidence of upper motor neuron degeneration,

Evidence of progressive spread of symptoms or signs within a region or to other regions,

Combined with the absence of:

Electrophysiological or pathological evidence of other disease processes that might explain the patient's motor neuron degeneration,

Neuroimaging evidence of other diseases that might explain the observed clinical and electrophysiological signs.

While the diagnosis of ALS has historically been primarily clinical, electrodiagnostic studies can further support the diagnosis if the clinical picture is unclear. Electromyography (EMG) is useful in detecting the findings of acute denervation (fibrillation and positive sharp waves), chronic denervation (long-duration, complex motor unit action potentials [MUAP]), and chronic reinnervation (large amplitude MUAP).[24] Nerve conduction studies will show normal sensory action potentials.

The Awaji criteria also include fasciculation potentials as evidence of acute denervation, along with the previously established electrodiagnostic signs, fibrillation, and sharp waves. In addition, electrodiagnostic evidence is considered of equal weight to clinical exam findings of lower motor neuron abnormality. These changes increase sensitivity while preserving specificity from the revised El Escorial criteria.[25]

Motor nerve action potential amplitudes may be low before weakness is clinically evident.[26] To be indicative of ALS, needle EMG must show signs of acute or chronic denervation in at least three spinal levels (bulbar, cervical, thoracic, and/or lumbosacral). If three spinal levels are not abnormal, acute or, chronic denervation needs to be evident in three extremities with the involvement of at least two muscles supplied by two different roots and two different nerves in each extremity.

The World Federation of Neurology (WFN) has also set forth categories that aid in the description of ALS. Although the verbiage would seem to imply degrees of certainty, these categories instead reflect the degree of clinical involvement evident at the time of an examination. They are as follows:

Clinically definite ALS: UMN and LMN signs in at least 3 body segments.

Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs.

Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by EMG in at least two limbs.

Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs.

Clinically suspected ALS: Pure LMN syndrome with other causes of LMN disease adequately excluded.

Neither the El Escorial nor the Awaji criteria include specific radiologic findings in their diagnostic models. Therefore, while the role of radiology in the evaluation of ALS is mainly the exclusion of other possible etiologies of a patient's clinical picture, a few subtle imaging findings have been associated with the upper motor disease found in ALS. Neuroimaging of ALS relies solely on magnetic resonance imaging (MRI). Studies have shown patients with ALS to demonstrate iron accumulation within the precentral gyrus.[27] As a result, on susceptibility-weighted imaging, the decreased signal is visible across the precentral gyrus, which is known as the "motor band sign."[28] On conventional MRI, decreased signal intensity within the motor cortex on T2 weighted images has been associated with ALS and may be used to support the diagnosis. In addition, well-defined lesions of increased signal intensity can be visible within the corticospinal tracts on T2WI.

Findings indicative of upper motor neuronal disease have also been elucidated utilizing advanced MRI techniques such as spectroscopy and diffusion tensor imaging (DTI).[29] MR spectroscopy can detect and quantify chemical concentrations, specifically of N-acetyl aspartate (NAA), choline, and creatine within imaged tissues. Multiple studies have demonstrated decreased absolute and relative quantities of NAA in patients with ALS.[30][31][30]

Once the diagnosis has been established, genetic testing is encouraged, particularly for the SOD1 and C9ORF72 genotypes, due to emerging genotype-specific therapies in clinical trials. For patients who have a family history of the autosomal dominant disease, genetic testing can be used both as a screening tool and to provide prognostic information. For patients who have a family history of unclear inheritance, genetic testing can be useful to elucidate reduced penetrance or when information about family members is limited.

Treatment / Management

Unfortunately, symptomatic management is the main treatment in patients with amyotrophic lateral sclerosis, and it is recommended that their care team be interprofessional, with caregivers from neurology, physical therapy, occupational therapy, respiratory therapy, dietary, social work and nursing.[32]

Patients with ALS commonly suffer from chronic respiratory failure due to weakness of the diaphragmatic and intercostal muscles. As this weakness is progressive, it is recommended to have an early, careful discussion regarding respiratory management and future options such as tracheostomy, chronic ventilatory support, and noninvasive positive pressure ventilation (NIV). This discussion should be continuous, as it is expected that patients will change their opinion during their disease. Noninvasive ventilation is considered when orthopnea, nocturnal hypoxia, or a forced vital capacity (FVC) <50% present. Invasive ventilation is considered when NIV is not tolerated, or when the patient remains hypoxic and/or hypercarbic despite NIV. It is also important to offer appropriate information about terminal stage ALS when dyspnea and nocturnal hypoventilation begin, or when vital capacity (VC)<50% of predicted values. Patients should be made aware of palliative options for symptom control like anxiolytics, opiates, and/or sedation, as fears of "choking to death" are common.[33] Patients usually become symptomatic when VC <50%. When VS reaches <25% to 30%, there is a high risk of respiratory failure or sudden death. Hypoxia and hypercarbia are late findings that physicians should not rely on to predict the need for respiratory support.[34]

Progressive weakening of the muscles of mastication and swallowing results in dysphagia, which should be managed initially with diet modifications. As weight loss (particularly within the first two years after diagnosis) is associated with worse prognosis, emphasis should be placed on the intake of calorically dense foods and supplemental nutritional beverages.[35] As the dysphagia worsens, the risks of aspiration and weight loss increase. Numerous studies have demonstrated the efficacy of enteral nutrition via percutaneous gastrostomy, and it should be considered in patients with impaired oral intake. However, as there is no significant evidence regarding the impact of gastrostomy tube (G-tube) placement on quality of life, it should be an individualized discussion and decision. If the patient decides to have a G-tube placed, it should be done before the VC becomes <50% predicted value to avoid increased morbidity with the procedure itself.[36]

As the disease progresses, there will be increased dysarthria and the eventual impossibility of communication. As this can be frustrating to patients, with limited benefits found in speech therapy, the patient should choose an appropriate alternative communication method (writing, alphabet boards, electronic assistive communication devices).[37]

Frequent and painful muscle spasms can be treated with mexiletine, which was well-tolerated and demonstrated good symptomatic response at a dose of 150 mg BID. in a small sample study.[38][39] Other options are levetiracetam and with less efficacy gabapentin, baclofen, and tizanidine.[40] The latter two of which have shown efficacy in the management of spasticity. When oral therapy is not effective or well-tolerated, botulinum toxin injections into the spastic muscles can be useful. As weakness and functional decline inevitably progress, patients should be provided 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.[33]

Sialorrhea is very common and can be treated with atropine (0.4 mg q4-6h), hyoscyamine, amitriptyline (10 to 150 mg QHS), glycopyrrolate (1 mg TID), botulinum toxin injections into salivary glands, and even low-dose radiation therapy in those with refractory symptoms.[32][41][32]

Pseudobulbar affect (episodes of uncontrollable laughter or crying) can affect up to 50% of patients with ALS, especially those with the bulbar form. In these patients, AVP-923 (dextromethorphan-quinidine 20mg/10mg) has proven to be effective in a multicenter, randomized, double-blind, controlled clinical trial.[42] Less rigorous evidence has supported the use of amitriptyline and fluvoxamine in smaller trials.

Riluzole (50mg bid) is thought to reduce glutamate-induced excitotoxicity and is the only drug that has proven improved overall survival (74% vs. 58% placebo at 12 months) and survival without tracheostomy (57% vs. 50% at 18 months) in two multicenter randomized trials done in the late 90s. Similar to these studies exclusion criteria, AAN guidelines recommended using it in patients with definite or probable ALS by El Escorial criteria in whom other causes of progressive muscle atrophy have been ruled out, symptoms have been present less than 5 years, VC >60% of predicted, and who do not have a tracheostomy. Expert opinion has also suggested a potential benefit in patients who do not meet these criteria, specifically limited to aspiration prevention. Since the original trials, multiple class I trials have shown a modest effect with prolonged survival of 2-3 months, and multiple other lower-class trials showed that riluzole might be associated with prolonged survival from 6 to even 21 months. Overall, it is considered a safe medication, and AAN guidelines recommend offering it to patients.[36] It is important to note that the elimination of riluzole will be affected by CYP1A2 inhibitors like caffeine and theophylline. Transaminase elevation is expected in about 50% of patients, and it is recommended to monitor transaminases monthly for the first three months and every three months afterward.

Edaravone is a free radical scavenger that is thought to reduce oxidative stress and has proven to be beneficial on a subset of patients with early-stage (less than two years of symptoms, independently living, VC >80% and scores of 2 or more in all items of ALSFRS-R) probable or definite ALS. One study showed approximately 33% slower functional decline in patients at 24 weeks follow up.[43] It has the limitation of being very expensive at around $146,000 per year and is administered in 60 mg daily infusions for 14 days followed by 14 days off for the first cycle, and then 60 mg/day for 10 days and 14 days off for the subsequent cycles. Edaravone should be used with caution in patients with asthma as it can cause serious asthmatic reactions in up to 5%.

Pain is a commonly reported symptom of patients with ALS, arising from numerous causes including muscle cramping, spasticity, and as a result of decreased mobility. Spasticity should be treated specifically, as outlined above. Assistive devices such as special mattresses, pillows, and wheelchairs may help to prevent pain. Ultimately many patients require nonopioid analgesics and anti-inflammatory drugs, and when these fail, opioids become the mainstay of pain treatment.[44]

Depression has a significant effect on the quality of life in patients with ALS, and studies have shown that treatment can improve quality of life. While no controlled trials have evaluated the treatment of depression in patients with ALS, Amitriptyline is commonly used as it can also treat other symptoms such as insomnia, sialorrhea, and pseudobulbar affect.

The issue of end-of-life care, and advanced directives, should be broached soon after diagnosis. One of the most important discussions revolves around tracheostomy placement and mechanical ventilation. Due to increased caregiver burden and significant associated costs, very few patients with ALS in the united states (less than 10%) opt for invasive ventilation. Hospice care can provide many resources that are not available, or as readily available in the home and can increase the likelihood of a peaceful death.[45] Dyspnea and anxiety are two common complaints that can be treated with morphine, and lorazepam or diazepam, respectively.

Differential Diagnosis

Multiple diseases can mimic amyotrophic lateral sclerosis including, but not limited to: cervical myelopathy, multifocal motor neuropathy, myasthenia gravis, Lambert-Eaton syndrome, inclusion body myositis, benign fasciculation, monomelic amyotrophy, spinal muscular atrophy, spinal bulbar muscular atrophy, poliomyelitis or post-poliomyelitis syndrome, late-onset Tay-Sachs disease, motor neuron syndromes secondary to lymphoproliferative disorders and other cancers, intraspinal lesions, radiation spinal myelopathy, hexosaminidase A deficiency, cramp-fasciculation syndrome, neuromyotonia, radiculoplexopathy, thyrotoxicosis, and myopathies.[46][47][48][49]

Prognosis

The median survival is of 3 to 5 years; however, around 30% of patients are alive after five years of diagnosis and 10% to 20% after ten years. Factors associated with better survival include increased weight at diagnosis (mild obesity by BMI), younger age at onset, higher ALS functional rating scale score, FVC at presentation, and limb rather than bulbar symptoms.[50][51]

Complications

As mentioned in the treatment and management section, there are numerous complications associated with amyotrophic lateral sclerosis, including respiratory decline with eventual need for ventilatory support, dysphagia, dysarthria, malnutrition, spasms, spasticity, fatigue, functional decline due to muscular weakness, sialorrhea, thick mucus secretions and pseudobulbar affect. In addition, some complications may arise due to the less-common medications meant to manage symptoms of the disease itself. These side effects include gastrointestinal upset and arrhythmias in mexiletine, transaminitis and asthenia in Riluzole, and gait disturbance and headache in edaravone.

Postoperative and Rehabilitation Care

Rehabilitation

Rehabilitating individuals with ALS requires an interdisciplinary approach to address the broad scope of therapeutic needs. Early intervention is crucial to maximize functional mobility and longevity. Comprehensive initial assessments of balance, gait, muscle strength and tone, activity tolerance, and performance of activities of daily living (ADLs) guide interventions targeting specific deficits. Fall prevention strategies (including assistive devices and environmental modifications) and energy conservation techniques are needed as the weakness and fatigue that comes with the progression of ALS increase the risk for falls and further injury in these patients. Orthoses and adaptive equipment may also be utilized for these patients to further their independence with ADLs.

Collaboration among healthcare providers, therapists, and caregivers is vital for comprehensive disease management. Throughout the course of care, it is important to not only be mindful of the trajectory of the disease but to focus on problem-solving and maximizing the patient's comfort, functionality, and quality of life.[52][53]

Deterrence and Patient Education

Patients need to know that this disease causes the muscles to weaken, eventually to the point of paralysis. Patients should also be aware that the disease will get worse and ultimately lead to death. Unfortunately, there is no cure; however, numerous medications can help lessen the associated symptoms. Patients may begin to notice difficulty with fine motor skills, from speaking to writing, as well as with walking, and eventually breathing.

Enhancing Healthcare Team Outcomes

ALS is a disease that necessarily progresses to significant, multifactorial debilitation and eventually death. As the clinical entity of ALS is broad in its subclassifications, involving many potential separate systems and symptoms, there is no single, standard model of patient care. Rather, the care plan of each patient needs to take into account the degree of lower motor involvement and weakness, especially whether it has progressed to the respiratory muscles, upper motor neuron involvement/spasticity, degrees of dysarthria and dysphagia, as well as the presence of other potentially associated symptoms such as frontotemporal dementia and depression. While the composition of these care teams will undoubtedly change based on the presence and degree of these symptoms, the interprofessional team will usually include the following practitioners: Physician, occupational and physical therapists, respiratory therapists, dietician, speech pathologist, social worker, and case manager. When patients with ALS are cared for by such an interprofessional team, there have been significant, demonstrable benefits in both the quality of life, as well as the length of survival.[54][55] [Level 2]

References

Disclosure: Ryan Brotman declares no relevant financial relationships with ineligible companies.

Disclosure: Maria Moreno-Escobar declares no relevant financial relationships with ineligible companies.

Disclosure: Joe Joseph declares no relevant financial relationships with ineligible companies.

Disclosure: Gauri Pawar declares no relevant financial relationships with ineligible companies.

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Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig disease," is a neurodegenerative disease of the motor neurons. No single etiology has been proven; rather, multiple pathways (both heritable and sporadic) have been shown to result in unmistakably similar disease entities.

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Article explaining the pathophysiology of the disease, including research and studies made to find more information.

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Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and…

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Explanation of disease mechanisms and the role that The ALS Association plays in furthering research.

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Amyotrophic lateral sclerosis (ALS) attacks motor neurons (a type of nerve cell) in the brain and spinal cord. There are two types of motor neurons: upper motor neurons (UMNs) that send nerve fibers down the from the motor cortex in the brain (part of the brain that controls movement) to the spinal…

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The goals of ALS research, and explanation of current ALS clinical trials

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Access for All in ALS (ALL ALS)

The Accelerating Access to Critical Therapies for ALS Act of 2021 established a national clinical research consortium in 2023. ALL ALS is led by James Berry, MD, MPH, in collaboration with Suma Babu, MD, MPH, MBBS, and Dr. Paganoni, along with investigators at three other academic medical centers. The consortium collects and organizes samples and data from people with ALS and people at increased genetic risk for ALS.

"The goal of the consortium is to develop the largest data set and biosample repository from people living with ALS. This will lead to many discoveries," says Dr. Paganoni.

BrainGate Neural Interface System

Leigh Hochberg, MD, PhD, director of the Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital, is director of the BrainGate Consortium and clinical trials.

BrainGate is trying to determine if a device implanted in the brain can help people with ALS control assistive devices with thought. The technology is targeted to people who have lost the use of their limbs or their ability to speak, including those with neurologic diseases such as ALS and beyond.

In a recent clinical trial, BrainGate researchers tested an implantable brain-computer interface that helped a 45-year-old patient with ALS successfully communicate again. The interface "decoded" the patient's brain signals as he attempted to speak and used artificial intelligence to create a computer-generated version of his own voice.

Where do I find more information about clinical trials for ALS?

"This is the right time to engage with ALS research. Clinical trials and research studies can give people with ALS the best possible tools to fight the disease now. Your collaboration also will help develop more treatments in the future," says Dr. Paganoni.

Start by talking to your doctor, who can offer guidance about the most appropriate research options for your circumstances. For more details about research opportunities and updates about treatment options at Mass General Brigham:

Register for ALS Link, a newsletter with clinical care information from ALS experts at the Healey Center and updates about the HEALEY ALS Platform Trial and other research.

Working together, the outlook for ALS treatment is hopeful, says Dr. Paganoni.

"We need to keep the momentum going, with more funding, more initiatives, and continued participation from the ALS patient community, so that we can make progress together."

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Latest ALS Research and Clinical Trials | Mass General Brigham

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Get the latest information on important progress in ALS research. Learn how to enroll in ALS clinical trials at Mass General Brigham.

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Available medications for ALS patients their effects, mechanisms of action, and side reactions

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Current potential therapeutics of amyotrophic lateral sclerosis

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Amyotrophic lateral sclerosis (ALS) is a debilitating motor neurological disorder for which there is still no cure. The disease seriously jeopardizes the health and lifespan of adult populations. The authors extensively retrieved the current…

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4 medications to treat ALS and their delivery methods

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Studies all over the world, many funded by The ALS Association, are ongoing to develop more treatments and a cure for ALS. There are currently seven drugs approved by the U.S. Food and Drug Administration (FDA) to treat ALS and its symptoms: Qalsody, RELY

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Current treatment options, supportive therapy and its importance and effects, gene specific therapies, and stem cells

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Keywords: amyotrophic lateral sclerosis, ALS, motor neuron disease, MND, medication, therapy, supportive therapy, clinical trials, personalized medicine

2.1. Medical Treatment

2.1.1. Riluzole

For a long time, Riluzole (6-(trifluoromethoxy)-2-aminobenzothiazole) was the only treatment option available for patients with ALS. The targeted pathway was mainly aimed at the reduction of excitotoxicity, specifically the excitotoxicity of glutamate. The positive effect of Riluzole is thought to result from different actions. Firstly, its action as a sodium channel blocker on presynaptic neurons decreases glutamate release into the synaptic cleft. Furthermore, glutamate reuptake is increased through the activation of astrocytic excitatory amino acid transporter 2 (EAAT2) channels and, additionally, aminomethylphosphonic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors on postsynaptic neurons are inhibited noncompetitively. Lastly, gamma-aminobutyric acid (GABA) reuptake seems to be reduced and GABA receptors potentiated [ 27, 28, 29, 30, 31].

Riluzole was approved by the FDA in 1995 and subsequently the EMA in 1996. In the first study examining the treatment of ALS patients with Riluzole, 155 participants were included in a prospective, double-blind, placebo-controlled trial. The intervention group received a daily dose of 100 mg of Riluzole, the standard dosage still valid today. After a treatment period of one year, a significant delay of disease progression was shown [ 4]. A further multicenter double-blind and placebo-controlled study with 959 participants confirmed these results in 1996 [ 32], suggesting a survival benefit of two to three months in both studies. However, real-world analyses suggest a higher survival benefit, ranging up to 19 months [ 33]. Most importantly, the study was able to identify Riluzole as a generally well-tolerated drug and determined the side effects, including asthenia, nausea, gastrointestinal problems, as well as augmentation in hepatic enzymes.

The Riluzole drug was first developed as an oral tablet of 50 mg taken twice a day but given the fact that many ALS patients are struggling with dysphagia, the development of a bioequivalent oral suspension of Riluzole (5 mg/mL) was essential [ 34, 35]. Furthermore, recently, an oral-film formulation form of Riluzole has been developed that poses another option to simplify administration and ensure the continuation of medical treatment [ 36, 37].

2.1.2. Edaravone

After the approval of Riluzole, no new drug entered the market for years until, in 2015, Edaravone (3-methyl-1-phenyl-2-pyrazoline-5-one) was approved in Japan and South Korea. After its FDA approval in 2017, China's NMPA and Switzerland followed with admissions in 2019, Indonesia in 2020, and, finally, Malaysia and Thailand in 2021. Edaravone has been used in acute-phase stroke intervention in Japan for years [ 38] and was designed to reduce oxidative stress and neuroinflammatory response by scavenging free radicals [ 39, 40, 41]. Its use in ALS treatment is based on a randomized, double-blind, placebo-controlled phase III trial with 137 participants [ 42]. Inclusion criteria allowed only participants with early stage ALS defined as disease duration of two years or less, ALSFRS-R scores of at least two for every item of the ALSFRS-R, forced vital capacity (FVC) of 80% or more, as well as a probable or definite ALS diagnosis as defined by the revised El Escorial criteria [ 42]. Prior to that, a previous phase III trial had not shown any significant overall effect of this drug [ 5]. Significant treatment effects were only shown after post hoc subgroup analysis with the above-mentioned criteria for early disease, which were then used in the second phase III study [ 43]. Results from the second phase III trial were a 33% reduction of ALSFRS-R decline over the 24-week treatment period and significantly better scoring on the ALSAQ-40 (forty item ALS assessment questionnaire; quality of life assessment tool). However, further studies did not yield significant effects, again [ 44, 45]. Typical side effects of Edaravone treatment were bruising, gait disturbances, headaches, and skin conditions [ 5, 46, 47].

Up to date, Edavarone is applied intravenously at a dosage of 60 mg/day. While the first administration takes place over a period of 14 days, all following monthly cycles take place for ten days. However, the convenience of this therapy method is below the one of orally assumable medicine. In 2022, an oral suspension of 105 mg/day was approved by the FDA. Simultaneously, there is a phase III trial conducted by Ferrer (TRICALS) for evaluating the safety and potential efficacy of FNP122, another oral application form of Edaravone.

2.1.3. Sodium Phenylbutyrate and Taurursodiol

Most recently, Sodium Phenylbutyrate and Taurursodiol (also known as PB-TURSO or PB-TUDCA [tauroursodeoxycholic acid] (Sodium 4-pheylbutanoate and 2-[(3α, 7β-dihydroxy-24-oxo-5β-cholan-24-yl) amino] ethane sulfonicacid, dihydrate) have been released as a fixed-dose combination. This drug is currently approved by the FDA and in Canada and both substances were previously approved for medical use separately. While Sodium Phenylbutyrate can be used in the treatment of hyperammonemia due to urea-cycle disorders [ 48], Taurursodiol has its place in the treatment of chronic cholestatic liver disorders [ 49]. Both have been identified as inhibitors of neuronal apoptosis and their combined action is proposed to reduce neuronal cell death and oxidative stress by decreasing stress in the endoplasmic reticulum (ER) and mitochondrial dysfunction [ 50, 51, 52, 53]. FDA approval was then based on results from a phase II multicenter, randomized, double-blinded trial (CENTAUR) that tested the safety and efficacy of a fixed-dose combination in 137 participants [ 3, 54, 55]. The combination of both substances slowed down disease progression (measured by the ALSFRS-R) by about 25% compared to the placebo group, and initiation of PB-TURSO treatment at baseline resulted in prolonged median survival of about 6.5 months. A phase III trial for the fixed-dose combination is currently ongoing and the recruitment of 664 participants was completed in February 2023 ( NCT05021536). The most common adverse events during the phase II trial were diarrhea, abdominal pain, nausea, and upper-respiratory-tract infections. Gastrointestinal-related adverse reactions occurred more frequently during the first three weeks of treatment [ 3].

Sodium phenylbutyrate/Taurursodiol was designed as an oral suspension and produced as a powder mixed with room-temperature water. The correct dosage contains 3 g of sodium phenylbutyrate and 1 g of Taurursodiol; it is initially administered once a day for three weeks and then twice a day.

2.2. Supportive Therapy

Supportive and palliative care is highly important to patients but rarely focused on in research. Nonmotor symptoms involving neuropsychiatric, autonomic, gastrointestinal, and vascular systems affect between 5% and 80% of people with ALS [ 56]. Thus, symptomatic treatment forms an important part of therapy in ALS patients and must be adapted to the clinical course. This includes symptomatic medical treatment for certain symptoms such as mood disturbances, pain, and spasticity that are usually not specially approved for ALS ( Figure 1a). The combination of dextromethorphan hydrobromide (20 mg) and quinidine sulfate (10 mg) was FDA-approved for ALS in 2011 for symptoms of frontal disinhibition such as frequent, involuntary, and often sudden episodes of crying and/or laughing [ 57]. While physical, occupational, and speech therapy as well as robotic assistance can maintain patients' autonomy, nutrition and home ventilation therapy aim to conserve somatic wellbeing. Studies have shown that access to and care through a tertiary ALS center can be a positive predictor [ 58] and are associated with increased six-month survival as well as reduced time to noninvasive ventilation (NIV) and gastrostomy [ 59]. Counseling and palliative care need to be discussed ( Figure 1b). Access to palliative care can improve the quality of life of patients and primary caregivers [ 60]. End-of-life discussions are an important part of patient care, especially as there is evidence suggesting that these discussions are often conducted with delay [ 61, 62]. Psychotherapy can alleviate depression and anxiety as studies on palliative care suggest and should therefore be offered, but there are only a few ALS-specific studies on this topic [ 63, 64]. Physical and speech therapy, occupational therapy, and robotic help systems are only some ways to help maintain functionality and, therefore, patients' autonomy for as long as possible, increasing the perceived quality of life [ 16, 17, 18]. Meanwhile, nutritional therapy may help in maintaining body weight and avoiding excessive weight loss by changing the quality and quantity of calorie intake as well as the administration method [ 19, 20]. During the final disease phase, progressive respiratory failure is addressed by the implementation of noninvasive and invasive ventilation attempting to alleviate hypercapnic symptoms and, in some cases, prolong survival [ 21]. Until a satisfactory causative treatment is found, supportive therapy and efforts to improve symptomatic medication remain of the utmost importance during disease accompaniment.

Figure 1.

Schematic overview of supportive therapy for patients with ALS: Different aspects are highlighted: ( a) Symptomatic medical treatment, ( b) Counseling and palliative care, ( c) Mobility, ( d) Speech and swallowing, and ( e) Ventilation. Created by Meret Herdick with "BioRender.com".

2.2.1. Mobility

Physical and Occupational Therapy

An important part of supportive treatment for ALS patients is active and passive physical therapy ( Figure 1c). Moderate active physical therapy has been shown to have a positive impact on the stabilization and maintenance of physical activity and ALSFRS-R levels when compared to passive therapy [ 16, 65]. A frequently prescribed therapy in ALS patients, a combination of stretching and motion exercises, but also endurance and aerobic movement therapy, is considered to be safe to perform [ 66]. While no particular training has proven to be superior regarding results in functionality, respirational capacity, or overall survival, a combination of all of the above can have a positive effect on the perceived quality of life and reduce subjective fatigue [ 67].

As an extension of physiotherapy, positive psychological and physical effects have been reported for motor-assisted movement exercisers (MME). These devices are for patients with muscle stiffness or weakness and can be used for physical exercise in the domestic area. Reports have shown positive psychological and physical effects [ 68] and more than 50% of frequent MME users report increased general wellbeing and reduced feelings of muscle stiffness.

Occupational therapy generally focuses on daily function while assessing, for example, the necessity for assistive devices and developing status-adapted strategies for tasks of everyday life and energy conversion [ 69, 70, 71]. The benefit of occupational therapy in ALS has been shown in small-sample studies. Music therapy, for example, led to an improved quality of life [ 72] and a single-subject study showed marked improvements in quality of life when involving aquatic therapy [ 73].

Robotics

Developments of robotic assistance aim, among other things, to battle progressive mobility restrictions experienced during ALS patients' individual disease course ( Figure 1c). A questionnaire-based study found more than 70% of ALS patients to be in favor of establishing robotic technology [ 68]. The prospect of greater independence increased the number of patients interested in robotic assistance for simple tasks such as serving drinks or handling an electronic device patients preferred robotic over human assistance [ 68, 74]. Currently, there are robotic solutions supporting patient independence and autonomy in different areas.

Addressing decreased mobility of the upper limbs, there are single-task devices specialized in performing, for example, food intake (e.g., "My Spoon" or "Obi") [ 74]. Furthermore, robotic lightweight arms, either fixed to a stationary workstation or mounted to a wheelchair, allow more complex movements within a certain radius [ 75]. Beyond these, there are efforts to develop wearable robotics, assisting the patient's body movement by exoskeletal support. A recent study worked on a lightweight wearable robotic device for assisted shoulder movement of patients with ALS, in which the device was able to compensate for continuing physical deterioration in 2 of 10 evaluated participants for a period of six months [ 76].

Exoskeletal approaches to compensate for lower-limb weakness and the related immobility are, for now, not focused on in ALS cohorts. Based on a recent review of wearable robotic exoskeletons in patients with spinal cord injuries, there are remarkable technological challenges that might impede effective everyday use in ALS patients. For example, the mean wearing time of different exoskeletons was around 10 min, and data regarding long-term use beyond 24 weeks is missing [ 77]. Generally, control of exoskeleton robotic systems can be realized through position, force, and speed sensors, or by using electromyographic (EMG) or electroencephalographic (EEG) signals [ 78]. Electrical wheelchairs are established tools for mobility in patients with different neurological diseases and are known to increase the quality of life and comfort while decreasing pain in ALS patients [ 79, 80]. Addressing the topic of steering without the necessity of precise fine motor skills, electromyographic surface sensors applied to temporalis muscles as well as autonomous navigation have been tested successfully [ 81, 82, 83]. Furthermore, electric wheelchairs controlled via eye-tracking devices are being investigated and there are already commercially available products on the market [ 84, 85, 86, 87]. In patients with severe disability and limited motor function, electrically adjustable beds can help with changing posture, especially when coupled with an eye-tracking system such as the "Environment Control in Amyotrophic Lateral Sclerosis (ECO-ALS) System" [ 88].

The field of robotics is also highly interesting regarding the topic of bulbar symptoms. For patients with the beginning of impairment of speech and preserved ability to use a touchscreen communication device, early access has been shown to positively influence the quality of life and may be especially helpful in improving communication skills in advanced disease stages [ 89]. An increased quality of life can be observed in severely dys- or anarthric patients when enabled access to eye-tracking devices for communication purposes [ 17]. During the last years, research has further focused on brain-computer interfaces which work independently from the residual motor activity and record neuroelectric signals in the brain [ 90]. Though not in standard clinical use yet, the first successful demonstrations of home use have been described, mainly for communication [ 91, 92, 93, 94].

There are constant efforts for technological improvement in order to help preserve patients' independence; however, there are few studies objectifying the benefits and possible disadvantages of robotics. We found no study or clinical trial regarding a possible positive effect on disease progression and survival, even though one could hypothesize, that patients with access to robotics, for instance by using an electrical wheelchair with resulting passive joint movement, may have a survival benefit when compared to advanced-stage patients with impaired mobility or bed-bound patients. This fact should be taken into consideration for future studies, as technological improvement might help in maintaining autonomy.

2.2.2. Speech and Swallowing

Speech Therapy and Communication Devices

Most patients develop bulbar symptoms such as dysarthria and dysphagia during their individual disease course [ 95]. Speech therapy is not only a valuable therapeutic component of disease management but can be an effective method to screen for dysphagia as well ( Figure 1d) [ 95, 96, 97]. Therapists can help by teaching adaptive eating strategies and adjustment to communication devices in advanced dysarthria or anarthria. Unfortunately, studies evaluating the benefit of speech therapy in ALS, and progressively dysarthric patients in general, are rare. A British survey further elucidated the lack of validated treatment guidelines for speech therapists in progressive dysarthria [ 98]. The speech therapy's effect alone is smaller than the effects and benefits of communication devices themselves when looking at the quality of life in late dysarthria stages, indicating the importance of high-technology communication devices as a source for quality of life [ 99].

Nutritional Therapy

Numerous publications have discussed nutritional therapy and its impact on overall survival in ALS patients. While antioxidant or anti-inflammatory nutrients might be beneficial in nutritional therapy [ 100], most studies focus on weight or body mass index (BMI) loss as an adverse prognostic factor [ 101, 102]. Patients with ALS often show a decrease in body mass years before symptom onset [ 20] and weight loss from disease onset to diagnosis is associated with a reduced overall survival [ 103, 104]. Not only do patients struggle with reduced oral caloric intake due to dysphagia but are frequently affected by hypermetabolism, intestinal problems due to medication intake, and loss of appetite [ 105, 106]. Thus, malnutrition and underweight can be caused by a combination of several factors, all leading to higher morbidity and mortality.

While patients presenting a bulbar phenotype are more often affected by dysphagia and, therefore, malnutrition and underweight, it has been observed that patients with a rapidly progressing spinal phenotype, but no signs of dysphagia, can suffer severe weight loss, a similarly poor prognosis and early need for ventilation [ 103]. Again, this fact highlights the complexity of weight decline in motor neuron diseases.

The ESPEN guidelines for neurological diseases, therefore, suggest a 3-monthly follow-up for nutritional status, BMI calculation and dysphagia screening [ 107]. Depending on the baseline BMI, weight gain (when BMI is <25 kg/m ²), maintenance of body weight (when BMI is between 25-35 kg/m ²), or weight loss (when BMI is >35 kg/m ²) are recommended. The calorie intake is suggested to be around 30 kcal/kg body weight and reduced to 25-30 kcal/kg when patients are ventilated noninvasively. In a randomized and double-blinded placebo-controlled study on the LIPCAL-ALS cohort published in 2020, a high-caloric fatty diet was examined for its effect on overall patient survival and also on vital capacity (VC), quality of life (Schedule for the Evaluation of Individual Quality of Life, SEIQoL), BMI, and appetite (Council on Nutrition Appetite Questionnaire, CNAQ) [ 20]. A significant increase in BMI, as well as an increased survival probability in a subgroup of fast-progressing patients (according to ALSFRS-R point-loss per month), could be objectified. It remains, however, a matter of discussion as to whether the fatty diet or the increased caloric intake is to be held responsible for this effect. Up to this day, there is no consensus on what kind of high-caloric nutritional therapy should be suggested in general.

As disease progress, bulbar symptoms, dysphagia, and general weakness for oral nutrition can worsened. In this case, initial support such as high caloric supplements, thickening of liquids and chaperoned swallowing training are not anymore able to compensate for weight loss or swallowing difficulties. Nutrition via a percutaneous gastrostomy (PEG), radiologically inserted gastrostomy (RIG), or nasogastric tube (NGT) must then be considered [ 19]. Given that ALS is a progressive disease and nasogastric feeding is associated with higher numbers of intervention failures, as well as a reduction of well-being resulting from, among other things, sensory irritations, NGT is primarily a bridging option until PEG or RIG are established [ 108, 109]. Nutrition via PEG is associated with prolonged survival; the timing of PEG insertion, however, remains a matter of discussion [ 110, 111]. Although clinical practice suggests insertion while predicted FVC is above 50%, Bond et al. have demonstrated a survival benefit for those with predicted FVC above 60% at tube placing time [ 110]. In addition, PEG insertion prior to significant weight loss has been associated with a prolonged tracheostomy-free survival [ 112]. However, there was no difference in disease duration between patients with different PEG placement timings according to their disease duration [ 110]. Interestingly, PEG feeding did not have a significant effect on patient mood measured by the clinical impression of mood [ 110].

2.2.3. Ventilation

Ventilation marks one of the basic therapeutic options in the symptomatic treatment of patients affected by ALS, especially during later disease stages ( Figure 1e). Most patients do not show respiratory symptoms upon diagnosis but develop diaphragm muscle wasting during the course of the disease [ 2]. The resulting hypercapnia can lead to sleep disorders with daytime sleepiness, fatigue, and severe impairment in quality of life [ 113, 114].

Parameters such as FVC, VC, peak cough flow, and, in patients with bulbar symptoms, sniff nasal pressure (SNP) are easily measured upon clinical visits. Additional blood-gas analyses or nocturnal measurements of oxygen saturation can be helpful for the decision-making and monitoring of implemented NIV therapy [ 19]. NIV initiation is recommended, according to the EFNS guidelines, when either clinical symptoms develop or FVC drops below 80% [ 19]. However, positive effects can be observed in asymptomatic patients not fulfilling these criteria, and cough-assisting devices helping bronchial clearance can maximize them [ 19, 113]. Certainly, given patient consent, the benefit of NIV therapy is undiscussed, considering prolonged survival rates in frequent users [ 21, 115, 116]. Increased survival time is strongly associated with the usage duration per day. One study found increased survival rates for patients with a minimum of four hours of NIV per day, when adjusted for confounding predictors of survival [ 117]. Apart from the known survival benefit, there is evidence for improved quality of life associated with NIV therapy [ 21, 118, 119].

There are remarkable regional differences concerning the rate of invasive ventilation implemented in ALS patients. While in most European countries invasive ventilation via tracheostomy is performed in about 10% of patients, studies from Asian countries often report over 20% [ 120]. Studies from different countries and continents consistently report prolonged survival in invasively ventilated patients and the effect is greater in younger patients, patients without signs of Frontotemporal Dementia (FTD), and spinal onset phenotypes [ 120, 121]. Unfortunately, few studies have been performed on the quality of life after tracheostomy in ALS, which might be impaired by the need for intensive 24-h care and the initial loss of vocal communication [ 121]. Due to the invasive nature of this ventilation method, it is important to discuss all potential risks and benefits with patients and their caregivers prior to tracheostomy [ 122]. The involvement of primary caregivers in invasive ventilation has been shown to be especially important [ 123].

3.1. Therapies Currently Being Tested

As various trials aiming for new drug validation are taking place at the moment, we attempt to highlight some of the latter, focusing on the different techniques and the targeted pathways [ 11, 15, 124]. In this review, ongoing trials are divided into four distinct groups: (1) development of small molecules, (2) gene-specific therapies, (3) monoclonal-antibody therapies, and (4) stem-cell therapies. The different targeted pathways and therapeutical approaches currently evaluated in clinical trials discussed in this review are resumed in Figure 2 and Figure 3 and listed in Table 1.

Figure 2.

Small molecules in phase II/III and III clinical trials, grouped by mode of action: ( a) Excitotoxicity, ( b) Oxidative, ER, and mitochondrial stress, ( c) Neuroinflammation, ( d) Autophagy and Proteostasis, ( e) Neuronal death, muscle denervation and weakness, and ( f) Bioenergetic metabolism. ER: Endoplasmic reticulum. Created by Laura Tzeplaeff with "BioRender.com".

Figure 3.

Gene, antibody, and stem-cell therapeutic approaches: ( a) Antisense oligonucleotides, ( b) Viral vectors delivering RNA interference or CRISPER/Cas9, ( c) Monoclonal antibody, and ( d) Stem cell transplantation. ANTX2: Ataxin-2; BM-MSC: bone-marrow-derived mesenchymal stem cells; C9orf72: Chromosome 9 open reading frame 72; FUS: Fused in sarcoma; SOD1: Superoxide dismutase 1. Created by Laura Tzeplaeff with "BioRender.com".

3.1.1. Small Molecules

There are numerous ongoing studies regarding small molecule development, with a high number of them undergoing clinical phase III trials [ 15, 124]. In this part, we will mainly focus on molecules tested in phase II/III and in phase III clinical trials to examine drugs closest to possible approval. Each of these small molecules has a direct influence on several dysregulated pathways associated with ALS. Amongst them are glutamate excitotoxicity, oxidative stress, inflammation, autophagy, and metabolism, as well as neuronal death and muscle denervation and weakness. In order to give a short overview, we tried to group molecules according to the pathway they are the most closely related to ( Figure 2).

Excitotoxicity

As mentioned above ( Section 2.1.1), a main mechanism in treatment with Riluzole is targeting excitotoxicity, especially of glutamate. Apart from that, other phase III clinical trials are also aiming to reduce excitotoxicity in ALS ( Figure 2a). For example, cannabinoids have been shown to decrease spasticity, and are therefore used as symptomatic treatment in ALS [ 125]. Based on their protective effect on oxidative cell damage and excitotoxicity, MediCabilis CBD Oil ( NCT03690791) was tested in a single-center phase III clinical trial in a small sample of participants in Australia to further evaluate a possible disease-modifying effect [ 126, 127]. Furthermore, Memantine ( NCT04302870), a noncompetitive NMDA receptor antagonist used in the management of Alzheimer's disease, is currently being tested in a phase II/III clinical trial in the multiarm MND-SMART trial to help reduce excitotoxicity [ 128].

Oxidative Stress

Edaravone and Sodium Phenylbutyrate/Taurusodiol are, as mentioned before ( Section 2.1.2 and Section 2.1.3), mainly associated with the reduction of oxidative stress.

Currently, four other drugs with this mechanism are being tested in phase III clinical trials ( Figure 2b). Trazodone, an approved drug for the treatment of depression, is tested in a phase II/III trial as part of the multiarm MND-SMART trial mentioned above ( NCT04302870) [ 128]. This drug inhibits protein kinase ribonucleic acid (RNA)-like ER kinase (PERK) and reduces the formation of stress granules [ 128]. In cellular and ALS animal models, the inhibition of PERK showed a reduction of TDP-43 (transactive response DNA-binding protein 43 kDa) toxicity, and Trazodone was associated with a decreased production of toxic proteins [ 129, 130]. Furthermore, Pridopidine is a Sigma-1 receptor agonist that increases brain-derived neurotrophic factor secretion and is suggested to enhance axonal transport and promote neuronal survival in a superoxide dismutase 1 (SOD1) mouse model [ 131]. Pridopidine ( NCT04615923) is investigated as part of the phase II/III multiregimen HEALEY ALS platform trial ( NCT04297683). Deferiprone ( NCT03293069), also tested in a phase II/III clinical trial, is a chelator and, therefore, is able to reduce iron accumulation and the related excessive oxidative stress in motor pathways [ 132]. Huolingshengji granules ( NCT04950933), currently in a clinical phase II/III trial, are a traditional Chinese herbal medicine formula that consists of six herbs that demonstrate reduction of oxidative stress in ALS cell and mouse models [ 133, 134].

Neuroinflammation

Among the drugs in clinical phase III targeting neuroinflammation, we can count six different trials ( Figure 2c). Some trials were recently stopped in phase II/III due to their lack of benefit in ALS patients. Zilucoplan ( NCT04436497), stopped in mid of June 2020, and Ravulizumab ( NCT04248465), stopped in January 2023, are both inhibitors of complement component C5, a part of the immune-response pathways. One might conclude that C5 is not to be a plausible target in ALS. However, neuroinflammation as a target for new molecules includes studies on Triumeq ( NCT05193994) as well. It is a repurposed drug combination of dolutegravir, abacavir, and lamivudine, used in HIV treatment and chosen for its anti-inflammatory and anti-HERV (human endogenous retroviruses) antiviral qualities, which are currently being tested in an Australian ALS multicenter phase III trial [ 135]. MN-166 (Ibudilast, phase IIb/III trial) ( NCT04057898) is a small molecule with the ability to inhibit proinflammatory cytokines in activated glial cells and several other mechanisms targeting neuroinflammation [ 136]. MN-166 is further believed to enhance autophagosomal synthesis and autophagosome-lysosome fusion, as shown in a cellular study [ 137]. Masitinib ( NCT03127267), a tyrosine kinase inhibitor targeting, in part, mast cells and microglial cells, aims to reduce neuroinflammation and modulate the neuronal microenvironment in both the central and peripheral nervous systems [ 138, 139]. Masitinib is currently tested in a confirmatory phase III trial ( NCT03127267) in a group of early disease stage patients with moderate functional impairment at baseline and is expected to have the greatest treatment effect in this group, as previously established from a phase III trial with broader inclusion criteria [ 138, 139]. The phase II/III multiregimen HEALEY ALS Platform Trial also evaluates Verdiperstat ( NCT04436510), a molecule that inhibits myeloperoxidase. In the literature, inhibition of myeloperoxidase results in reduced motor impairment and microglia activation, decreasing neuroinflammation in a mouse model [ 140]. According to the observation of post mortem human brain tissues, this drug could have a greater effect on patients with SOD1 mutation [ 141].

Others

Apart from excitotoxicity, oxidative stress, and neuroinflammation, other ALS-linked disease mechanisms have been targeted in clinical trials. Boosting autophagy and direct action on protein aggregation are some of the paths pursued in alternative approaches. Arimoclomol ( NCT03836716), a drug that increases heat shock protein production and enhances autophagy, did not meet its primary or secondary endpoints of impact on function or survival, and the corresponding trial was terminated in July 2021. For now, not much is known about the results of this terminated study. Hopefully, the planned publication will allow insight into potential improvements and changes in future clinical trials targeting autophagy. Parallelly, other clinical trials targeting autophagy are still ongoing and look promising. Amongst those, Trehalose ( NCT05136885), a disaccharide, is currently being tested as part of the HEALEY ALS Platform Trial in a phase II/III trial in the USA [ 142, 143]. It is capable of enhancing autophagy and decreasing SOD1 mutant aggregates in mice.

One phase III trial is currently testing a fast skeletal muscle troponin activator, Reldesemtiv ( NCT04944784). This drug is a small molecule designed to slow the release of calcium during muscle contraction, improving muscle function and movement. In phase IIb, a benefit for Reldesemtiv could be demonstrated over time, when measuring the revised ALS functional rating scale (ALSFRS-R) and the slow vital capacity, especially at the study endpoint of 12 weeks. The authors postulate that the magnitude of the effect of Reldesemtiv could be even greater after a longer period of treatment [ 144]. However, this trial has been discontinued on 31 March 2023 due to futility, as no further evidence of positive effect had been observed on the primary and secondary endpoint after 24 weeks in patients treated with Reldesemtiv when compared to placebo-treated patients.

Methylcobalamin ( NCT03548311), a form of vitamin B12, when used in an ultrahigh dosage, was found to reduce denervation and reduce muscle weakness in a mouse model [ 39]. The results of the clinical phase III trial demonstrate similar positive results in humans with a slower functional decline in patients with early-stage ALS and having a moderate progression rate [ 145].

Insulin-like growth factor-1 ( NCT00035815) is a neurotrophic factor essential for the nervous system's development and can, as shown in animal models and cell culture systems, have a protective effect on neuronal cells [ 146, 147, 148, 149]. This effect is, supposedly, due to the blockage of cell-death pathways and promotion of muscle reinnervation as well as axonal growth and regeneration. However, results from a two-year phase III study concluded no benefit for ALS patients concerning survival time or muscle weakness [ 150]. To note, this study did not investigate the effect of IGF-1 on subgroups of patients concerning, for example, familial SOD1 mutations. Indeed, to our knowledge, the positive effect of IGF-1 was not investigated in any other model than SOD1 mouse models [ 146, 147, 148, 149].

CNM-Au8 ( NCT04615923) is another drug investigated as part of the phase II/III multiregimen HEALEY ALS Platform Trial. This molecule is a gold nanocrystal acting on energy metabolism and was developed by Clene Nanomedicine. This drug catalyzes the oxidation of NADH into NAD+ and increases the production of ATP to reduce oxidative stress in a mouse model [ 151].

To conclude the part on small molecules, there are many more clinical trials currently ongoing, either in phase II or I, and not detailed in here but nicely described in other recent reviews [ 11, 15, 124]. There are high expectations from current trials of small molecules, particularly for phase II/III trials approaching several new molecules at the same time. Examples are the multiregimen HEALEY ALS Platform Trial (estimated completion date: April 2026) or the multiarm MND-SMART (estimated completion date: December 2026) trial.

3.1.2. Gene-Specific Therapies

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are single-stranded synthetic oligonucleotides that can be designed to complement specific mRNAs and induce their degradation. ASOs have caused widespread media attention, with the FDA approval of Nusinersen and Eteplirsen in 2016 for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy that revolutionized the treatment of these two diseases [ 152, 153]. Thus, ASOs can be a powerful treatment approach in single-gene mutation diseases and could also be beneficial in ALS patients with specific gene mutation ( Figure 3a) [ 154]. The first phase III trial further elucidating ASOs in ALS with SOD1 mutation examined Tofersen ( NCT02623699; BIIB067), a drug applied intrathecally. Based on promising subgroup analyses from phase I and II trials, the VALOR (Part C) trial was performed [ 155]. While the ALSFRS-R levels in ALS patients did not differ significantly between the trial and placebo groups after 28 weeks, SOD1-levels in cerebrospinal fluid (CSF) and neurofilament light chain (NfL) levels in plasma lowered significantly [ 156]. Adverse events were most often related to lumbar puncture [ 156]. Of note, in this study, participants receiving Tofersen during earlier disease stages showed a smaller decline in ALSFRS-R score than those that had started Tofersen during the open-label extension phase. Based on this observation, participants are monitored in a long-term evaluation trial with expected completion in July 2024 ( NCT03070119). A study analyzing the effects of Tofersen in presymptomatic genetic SOD1 mutation carriers has been launched (ATLAS; NCT04856982) and expanded access programs enable global access for eligible patients ( NCT04972487). To note, the ALS population with mutant SOD1 represents 15-20% of fALS and approximately 3% of sALS. Thus, this strategy could be beneficial to a significant part of the ALS population and represents a big step forward in ALS therapy.

Developed for patients with fused in sarcoma ( FUS) gene mutations, ION363 is currently undergoing a phase III trial as well. The drug is applied intrathecally [ 157]. Autopsy results of the first application in a human suggested reduced FUS pathology due to the treatment [ 157]. Several other patients have therefore been treated in the expanded access program. The ongoing phase III trial (FUSION; NCT04768972), a placebo-controlled trial with a 2:1 ratio of investigational medical products to placebo, includes a "rescue" option that allows moving participants into the open-label extension phase in case of significant functional decline during the placebo-controlled study-observation period.

Further treatments that involve ASOs are currently being tested but have not reached phase III yet. A phase I clinical trial on IIB078, an ASO targeting C9orf72 (chromosome 9 open reading frame 72), has been stopped due to its lack of efficiency and reported worsening of symptoms in C9orf72 ALS patients (NCT03626012B). While SOD1 and FUS ALS patients, respectively, demonstrate an abnormally high amount of SOD1 and FUS protein, C9orf72-ALS patients, in contrast, demonstrate haploinsufficiency. In C9orf72-ALS patients, the RNA production from the C9orf72 gene, not the protein itself, is toxic [ 158, 159]. Thus, reduction of the C9orf72 protein with ASO might not work for this subgroup of ALS patients. However, another ongoing phase I/II clinical trial has been initiated on WVE-004, using a different ASO technology. For this trial, the ASO is targeting transcriptional variants containing hexanucleotide repeat expansion without affecting the protein level of C9orf72 ( NCT04931862). BIIB105 is being tested in a phase I trial for participants with Ataxin-2 (ATXN2) repeat expansion ( NCT04494256). ATXN2 is usually associated with Spinocerebellar Ataxia Type 2 (SCA2), causing the disease by an expansion of CAG triplets above a length of 22-23 repeats [ 160]. While repeat expansions above 35 are associated with full penetrance for SCA2, Elden et al. discussed an association of intermediate lengths of 27-33 repeats with ALS [ 160, 161]. Targeting ATXN2 induces the reduction of TDP-43 and showed improved motor function and survival in mouse models, which is why BIIB105 could be beneficial for both patients with and without Ataxin mutations, lowering the TDP-43 protein level [ 162].

Viral Vectors Delivering RNA Interference and CRISPR/Cas9

Viral vectors, for example, nonpathogenic adeno-associated viruses (AAVs), have the ability to transport exogenous molecules into cells. This mechanism can be used to deliver therapeutic agents into cells of the central nervous system (CNS). In contrast to therapeutic approaches based on ASOs, micro-RNA- or CRISPR/Cas9-containing vectors would only be injected once [ 163].

RNA interference is a biological mechanism initiated by the presence of short double-strand RNA (dsRNAs). Once dsRNAs are detected, they are degraded into micro-RNA (miRNA) or small interfering RNA (siRNA) and incorporated into the RNA-induced silencing complex (RISC). This RISC complex can then degrade the complementary mRNAs of the microRNA and thus prevent protein translation. Recent therapies design specific miRNAs to prevent the translation of ALS-linked proteins ( Figure 3b). For example, APB-102 (also named AMT-162) a SOD1 microRNA, delivered in AAVs and applied via intrathecal injection, was tested in two human patients [ 164]. Once incorporated into nervous cells, APB-102 targets and binds SOD1 mRNA, subsequently reducing its protein production. Not only the misfolded mutant SOD1 but also the misfolded wtSOD1 accumulate and aggregate in both familial ALS (fALS) and sporadic ALS (sALS) [ 165]. Thus, by reducing global SOD1, APB-102 may slow down ALS progression by reducing aggregation, improving the survival and function of motor neurons, and potentially providing a new therapeutic opportunity for ALS patients with SOD1 pathology. This approach could potentially give results similar to treatment with ASO against SOD1. However, the benefit of this approach is its convenience, avoiding readministration by performing a single injection. UniQure is currently acquiring the rights to develop this technique for phase I/II clinical trials, which is expected for the second half of 2023. Meanwhile, the company is also developing similar techniques to treat ALS patients with C9orf72 mutations using AMT-161 miRNA molecules. However, not much is known about this future product, and regarding the negative and detrimental result obtained with ASO treatment against C9orf72, we might expect an identical outcome when targeting global C9orf72 production. In 2022, at the 29th European Society of Gene and Cell Therapy (ESGCT) Congress, UniQure also presented AAV-miQURE ® results in an ALS C9orf72 mouse model [ 166]. This strategy selectively binds the mutant repeat expansion of C9orf72 mRNA, leading to the degradation of the toxic target transcripts without affecting native C9orf72 mRNA and protein. Up to now, this technique looks like a much more promising therapy.

Furthermore, viral vectors can also carry the CRISPR/Cas9 technology [ 167]. This gene-editing method is associated with a design RNA guide that enables the Cas9 endonuclease to cut at a desired genomic location and remove and/or add new genetic sections. The technique is not yet used in clinical trials; however, studies aiming to target SOD1 and C9orf72 pathogenic alleles on cell and animal models have been initiated [ 168, 169, 170].

In summary, ASO, RNAi, and CRISPR/Cas9 represent three different approaches to targeted gene therapy, offering opportunities for drug development for ALS patients with genetic mutations. AAV vectors can be used to mediate other gene delivery, for example, genes essential for neurotrophic support, or for modulating the neuromuscular junction. Thus, gene therapy is not necessarily limited to fALS but is also investigated for sALS, as reviewed by Amado et al., 2021 [ 163].

3.1.3. Monoclonal Antibodies

While there are no current phase III trials examining antibody treatment in ALS, there are interesting ongoing and completed phase II studies ( Figure 3c). Amongst those, one study is testing the human monoclonal antibody AL001 ( NCT05053035) in C9orf72-associated amyotrophic lateral sclerosis. AL001 binds the sortilin receptor and increases progranulin protein (PGRN) levels in C9orf72 ALS patients. In ALS mice models, progranulin demonstrates reduced TDP43 aggregation [ 171]. Furthermore, there is an ongoing phase III trial investigating AL001 in participants with heterozygous GRN (progranulin gene) mutations (INFRONT-3; NCT04374136), a causative mutation for FTD that is, in some cases, associated with ALS-FTD or pure ALS, as well [ 172, 173].

AP-101 ( NCT05039099), a human IgG1 antibody with high affinity and selective binding to misfolded SOD1 protein, is tested in a phase II trial on participants with both fALS and sALS, based on promising results from mouse models [ 174]. Further monoclonal antibodies are tested in phase II trials, aiming to reduce neuroinflammation (ANX005- NCT04569435, AT-1501- NCT04322149, Tocilizumab- NCT02469896). Further information is reviewed in Johnson et al., 2022, or Jiang et al., 2022 [ 15, 124].

3.1.4. Stem Cells

Stem cells, cells that-when guided into the desired direction by growth factors-can develop into any specific cell type, could function as a therapeutic approach in ALS. By developing into functioning neurons, these cells could replace damaged or apoptotic neurons. When injecting mesenchymal stem cells, the immune system could be guided towards an anti-inflammatory, neuroprotective environment by releasing different favorable soluble factors, instead of reacting to oxidative stress or degeneration by forming a proinflammatory, in parts toxic environment. There are different types of stem cells in use in preclinical and clinical trials. The most common among them are hematopoietic or mononuclear cells, neural stem cells, induced pluripotent stem cells, and mesenchymal stem cells. The latter is the most frequently investigated stem-cell type in human trials [ 175]. While preclinical studies showed positive effects in rodent models, mostly in presymptomatic animals, a gap for translation to an efficient trial culture in humans is yet to be filled [ 175]. While transient positive effects on clinical disease progression can be observed, patients demonstrated worsening in their respiratory function. Methodological challenges include (1) adequately big trial cohorts, (2) heterogeneity of eligible patient cohorts concerning their clinical and personal characteristics, (3) lack of placebo-controlled studies, and (4) the lack of publication of previously performed stem-cell trials [ 175]. There is a distinct need for large multicenter and placebo-controlled trials. Two studies on bone-marrow-derived mesenchymal stem cells (BM-MSC) are found in advanced trial stages in the context of ALS ( Figure 3d). NurOwn ® is available in an expanded-access protocol for patients who were enrolled in the preceding phase III trial. While the clinical endpoint was not met in the phase III trial, subgroup analyses of patients in early disease stages (ALSFS-R ≥ 35) as well as improvements of biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were promising ( NCT04681118) [ 176]. Lenzumestrocel (Neuronata-R ® Inj) ( NCT04745299), a BM-MSC as well, is currently being tested in a phase III clinical trial with an estimated enrolment of 115 participants, based on significant therapeutic benefits lasting at least six months in patients with ALS reported in the phase II trial ( NCT01363401) [ 177]. Beyond these, there are several other neuronal, monoclonal, and mesenchymal stem cell therapeutic strategies that are currently undergoing a phase I/II clinical trial [ 15, 124].

In conclusion, stem cells are an established treatment method in some hematological diseases, however, with numerous treatment-related risks. Results from the two ongoing phase III clinical trials will broaden knowledge of stem cells as a treatment option for ALS. However, the general challenges in trial culture, as discussed above, will have to be addressed before considering stem cells as a viable treatment option for ALS.

Table 1.

Approved Drug

Pathway

Phase

Therapeutic being tested (selection)

Pathway/Approach

Phase

3.2. Novel Therapeutic Approaches (Unaddressed or Poorly Addressed Yet)

We previously discussed the different clinical trials including molecules or techniques targeting certain ALS pathways. However, some ALS-dysregulated pathways are still unaddressed. In this section we will highlight different unaddressed mechanisms, amongst them post-translational modification (PTM), axonal transport, and others, discussing their potential benefit for future ALS treatment. These pathways are represented in green in Figure 4.

Figure 4.

Future strategies and approaches: ( a) Post-translational modification, ( b) Axonal transport, ( c) Nucleocytoplasmic transport, ( d) DNA damage, and ( e) Molecular tweezer. DNMTs: DNA methyltransferases; HDACi: histone deacetylase inhibitors; PARP: Poly ADP-ribose polymerase. Created by Laura Tzeplaeff with "BioRender.com".

3.2.1. Post-Translational Modification

Post-translational modifications (PTMs) impact proteins involved in the neuropathology of ALS, including FUS, SOD1, and TDP-43 [ 178, 179, 180]. Changes in acetylation, methylation, or phosphorylation are known to influence not only protein function but also their subcellular locations, interaction with other proteins or RNA, liquid-liquid phase separation, stress granule formation, cell death, as well as other processes [ 180, 181, 182, 183, 184]. A few strategies to target post-translational modification can be cited ( Figure 4 a).

Epigenetic mechanisms, including DNA methylation and histone modifications, are part of these PTMs and function as a key process in gene transcription regulation and DNA damage repair [ 185, 186, 187, 188, 189]. Recent studies have reported several dysregulations in histone PTMs in numerous ALS models, including alterations in acetylation, methylation, and phosphorylation, as well as global changes in epigenetic enzyme modifiers [ 190, 191, 192]. In order to revert these disease-associated alterations, most studies focus on the use of histone deacetylase inhibitors (HDACi) [ 193]. For example, the HDAC6 inhibitor is able to restore axonal transport and metabolic-lipidomic functions in ALS-FUS and ALS-TDP43 iPSC (induced pluripotent stem cells)-derived motor neurons [ 194, 195, 196, 197]. However, delivery to target and drug tolerance of HDACi are still improvable, as some show cytotoxic effects, depending on the cell type [ 198]. Interestingly, sodium phenylbutyrate, an HDACi, was recently approved by the FDA in combination with Taurursodiol, although the underlying mechanism in this context remains unclear [ 3]. Other studies report promising results when targeting protein and histone phosphorylation with commercially available kinase inhibitors, improving TDP43 localization and aggregation [ 182, 192, 199, 200]. Fasudil, a kinase inhibitor, is currently being tested in a phase II clinical trial for ALS treatment ( NCT03792490). As observed in ALS mouse models, it was able to restore the phosphorylation levels of certain proteins associated with synaptic and neuroinflammatory functions [ 201, 202].

Hope et al. recently detected changes in DNA methylation patterns in blood samples of more than 6.000 ALS patients worldwide and observed, that Riluzole was not able to revert specific DNA methylation changes in an efficient manner [ 203]. Motor neurons in human ALS show a significant increase in so-called DNA methyltransferases (DNMTs), responsible for DNA methylation production, as well [ 204]. Thus, inhibition of aberrant DNA methylation is a new direction that could possibly become relevant for new therapies for ALS. Some of these DNMT inhibitors are resumed by Martin et al., 2013 [ 205].

3.2.2. Axonal Transport

Targeting axonal transport is not completely unaddressed in clinical trials. Pridopidine ( NCT04297683), demonstrating enhanced axonal transport in a SOD1 mouse model, is currently being tested in a phase II/III trial [ 131]. As previously described, HDAC6 inhibitors can restore axonal transport defects in patient-derived motor neurons with FUS or TDP43 mutations. They are also able to restore axonal ER transport in the iPSC FUS model and mitochondrial transport in both FUS and TDP43 iPSC models [ 194, 197]. Interestingly, these two studies also demonstrated that HDAC6 inhibitors restore several other pathways altered in ALS, amongst them metabolic-lipidomic functions, aggregation, and subcellular localization. Since axonal transport interacts with other pathogenic mechanisms, restoring the latter might have an overall positive effect on disease progression ( Figure 4b) [ 206].

3.2.3. Nucleocytoplasmic Transport

Nucleocytoplasmic transport is poorly addressed in clinical trials but widely altered in ALS [ 207]. Inhibition of nuclear export or enhancement of nuclear import could be strategies to restore nucleocytoplasmic function in ALS ( Figure 4c) [ 208, 209, 210, 211]. The only clinical trial examining nucleocytoplasmic transport, that we are aware of, was implemented by Biogen. Here, BIIB100, a nuclear-export inhibitor targeting XPO1 ( NCT03945279), was tested; however, its phase I trial was terminated in June 2021 without clear reason.

3.2.4. DNA Damage

While the evidence linking excessive DNA damage to ALS is increasing, clinical trials acting on this pathway are lacking [ 212]. Modulating, for instance, the Poly ADP-ribose polymerase PARP1, a protein predominantly triggered by DNA damage, could have a positive effect on the disease. Generally, PARPs are enzymes that catabolize NAD+ to sequentially add adenosine diphosphate (ADP)-ribose subunits onto target proteins. This generates polymers of poly (ADP-ribose) (PAR). Interestingly, increased PAR was observed in the motor neurons of an ALS spinal cord [ 213]. Inhibition of PARP via Veliparib, an FDA-approved drug, decreases TDP-43 aggregation in culture cells and reduces TDP-43-associated neuronal loss in rat spinal cord cultures [ 213]. Olaparib, another FDA-approved PARP inhibitor, demonstrated a reduction of PAR levels and rescued TDP-43-induced death in culture cells. There are other approved PARP inhibitors that could be tested in the context of ALS [ 214]. Apart from PARP inhibitors, Fasudil and Cannabidiol (CBD), both previously discussed, are able to reduce the expression of PARPs ( Figure 4d) [ 215, 216].

3.2.5. Molecular Tweezer

Currently, most of the strategies regarding the inhibition of protein aggregation rely on the use of monoclonal antibodies, as previously discussed with AL001 ( NCT05053035) and AP-101 ( NCT05039099) clinical trials. A new interesting approach might be the use of small molecules, called molecular tweezers, which help in preventing the aggregation of toxic proteins ( Figure 4e). Molecular tweezers are host molecules with open cavities capable of binding molecules. For example, the CLR01 molecular tweezer acts as a nano chaperone that transiently binds abnormal protein self-assembly at positively charged amino acid residues (primarily lysine and to a lower extent arginine) and inhibits aggregates of multiple disease-associated proteins [ 217]. Thus, molecular tweezers work as a tool to target the process of abnormal protein self-assembly itself rather than a particular protein. The molecular tweezer CLR01 is able to decrease SOD1 aggregation in vitro and in vivo in the SOD1 mouse model [ 218, 219]. Unfortunately, this strategy did not succeed in slowing down motor symptoms. In contrast, CLR01 inhibiting Tau aggregation was able to ameliorate muscle-strength deterioration and anxiety- and disinhibition-like behavior in an Alzheimer's disease mouse model [ 220]. To our knowledge, CLR01 has not been tested in other ALS models than SOD1. CLR01 action in SOD1 is mainly explained by binding to lysine residues, and results vary depending on the type of mutation [ 218]. Since CLR01 also acts through arginine binding, and that FUS contains different arginine-rich regions, it is then tempting to speculate that CLR01's impact on the FUS-ALS model might have a different outcome than the one observed in the SOD1-ALS model. Neither was CLR01 tested in the C9orf72 model to test its efficiency on PR (proline-arginine), or GR (glycine-arginine) dipeptide repeat aggregation.

4.1. Clinical Characteristics

As a first step towards personalized trial culture, future studies will benefit from analyzing results depending on ALS subgroups. Overlaps of ALS with other diseases such as FTD or parkinsonism offer further possibilities for stratification [ 2]; 30-50% of ALS patients develop behavioral impairment, or criteria for FTD which is associated with worsened disease progression and shorter lifespan [ 1, 223, 224]. The phenotype, as well as overlap syndromes, show remarkable differences in overall survival. The pure lower motor neuron phenotype, for instance, has a median survival more than three times longer than the bulbar phenotype [ 225]. Multiple studies have identified the clinical phenotype as an independent prognostic factor and some have, at least in parts, included the phenotype as a prognostic factor into their model for prognosis [ 226, 227, 228]. Previous clinical trials demonstrated differences in treatment effectiveness depending on clinical phenotypes defined by disease onset or progression rate [ 4, 20]. Future studies should consider stratifying groups by their phenotypic manifestation. This might enhance the prediction of clinical progression rate (fast vs. slow), possibly resulting in improved statistical power.

4.2. Genetic Classification

Another strategy for subgroup division is stratification according to genetic mutations (for example, see Section 3.1.2 on gene-specific therapies). Overall, there are more than 30 genes known to cause fALS. The most common mutations affect C9orf72, SOD1, FUS, and TDP-43, differing in both clinical manifestation as well as treatment response [ 229]. Currently, so-called sporadic cases are occasionally not admitted to genetic testing, even though an empty family history does not exclude genetic alterations [ 229]. Not only de novo mutations, but also incomplete penetrance and phenotypic variability, presymptomatic disease stages in relatives, or even earlier, non-ALS-related death of mutation carriers can cause a falsely negative family history [ 230]. Grassano et al. found genetic alterations in 21.5% of sALS cases in a cohort of 1043 ALS patients and a genetic diagnosis in almost 27% of all individuals after having performed whole-genome sequencing [ 231]. It seems desirable to offer genetic counseling and routine genetic testing to all ALS patients at the time of diagnosis. Importantly, the results of genetic testing may require long waiting times, delaying possible treatment. Acceleration of genetic testing should be focused upon. When genetic alterations are present, relatives at risk may be offered genetic counseling as well as predictive testing. Presymptomatic monitoring and treatment possibilities for asymptomatic carriers may offer hope for thus far clinically unaffected individuals (e.g., ATLAS study for presymptomatic SOD1-mutation carriers- NCT04856982) [ 232]. As it is often suggested that disease evolution is gradual, presymptomatic treatment may prolong time-to-symptom onset as well as overall survival [ 233]. Importantly, all findings gained through genetic testing require interpretation by experienced professionals, calling for close interdisciplinary cooperation between geneticists and neurologists as well as extensive genetic counseling prior to testing.

4.3. The Power of Biomarkers

While studies on biomarker discovery mainly aim to accelerate and improve ALS diagnostics, enhancements in this field may also help in the prognostic evaluation as well as treatment-response monitoring. ALS patients experience progressive functional decline and limitations. The window for therapeutic opportunities remains relatively small. Therefore, early diagnosis is the key to early access to treatment and interventions. Here, a disease-specific biomarker (or biomarker panel) with high sensitivity and specificity for ALS would revolutionize diagnosis. The use of biomarkers for diagnostic and prognostic purposes in ALS is widely discussed in the review, which resulted from the Second ALS Young Investigators Academy [ 234]. In this section, we mainly address biomarkers that could be useful for treatment monitoring and patient stratification. Thus far, neurofilaments (Nf), proteins that can be found in myelinated axons, have been a matter of discussion as a main biomarker in ALS. The most frequently used blood-based biomarker is NfL [ 235]. In the case of neuronal/axonal damage, NfL levels increase in both CSF and blood and are highly correlated [ 236, 237]. There are efforts to establish NfL for monitoring pharmacodynamic treatment effects as well as prognostic classification. High levels of NfL have negative prognostic connotations [ 238, 239]; however, NfL levels remain relatively stable after disease onset, complicating its use as a prognostic marker for individual disease course after onset [ 238, 240, 241, 242]. In the recent phase III Tofersen trial, the primary clinical endpoint represented by ALSFRS-R decline was not reached, while significantly reduced NfL levels were observed. Nevertheless, a reduction of NfL level could be a sign of deceleration of disease progression [ 156]. For prognostic purposes as well as treatment monitoring, a combination of NfL with miRNA-181 derived from blood samples showed promising results [ 243]. Another example is TDP-43, taken from peripheral blood, which was correlated with time of generalization from bulbar or spinal symptoms to both regions. CSF pTDP-43 levels correlate with ALSFRS-R [ 244]. Furthermore, regulatory T cells have been investigated as markers of immune dysregulation with an inverse correlation to disease progression in ALS [ 245, 246, 247]. It may be interesting to investigate the regulatory T cells reaction to specific ALS treatments. Neopterin, a marker of proinflammatory state immune response, as well as p75, a marker of microglia and macrophage activation, both taken from urine samples, could be correlated to disease progression [ 248, 249]. Both biomarkers are especially interesting, as urine sampling is noninvasive and therefore feasible even in advanced disease stages. Similarly, tear fluid can be sampled noninvasively and has been the subject of a recent trial with promising results [ 250]. However, more studies in larger cohorts and longitudinal subsets are necessary in order to evaluate the benefit for therapy monitoring through biomarkers.

AAVs

Adeno-associated viruses

ADP

Adenosine diphosphate

ALS

Amyotrophic Lateral Sclerosis

ALSFRS-R

Revised ALS Functional Rating Scale

AMPA

Aminomethylphosphonic acid

ASO

Antisense oligonucleotide

ATXN2

Ataxin-2

BMI

Body mass index

CBD

Cannabidiol

C9orf72

Chromosome 9 open reading frame 72

CNS

Central nervous system

CSF

Cerebrospinal fluid

DNMTs

DNA methyltransferases

dsRNAs

Double strand RNA

EAAT2

Excitatory amino acid transporter 2

EEG

Electroencephalographic

EMG

Electromyographic

ER

Endoplasmic reticulum

fALS

Familial ALS

FTD

Frontotemporal Dementia

FUS

Fused in sarcoma

FVC

Forced vital capacity

GABA

Gamma-aminobutyric acid

HDACi

Histone deacetylase inhibitors

iPSC

Induced pluripotent stem cells

miRNA

micro RNA

MME

motor-assisted movement exercisers

Nf

Neurofilaments

NfL

Neurofilament light chain

NGT

Nasogastric tube

NIV

Non-invasive ventilation

NMDA

N-methyl-D-aspartate

PAR

Poly Adenosine diphosphate (ADP)-ribose

PARP

Poly ADP-ribose polymerase

PEG

Percutaneous gastrostomy

PERK

Protein kinase Ribonucleic acid (RNA)-like endoplasmic reticulum kinase

PGRN

Progranulin

PTMs

Post-translational modifications

RIG

Radiologically inserted gastrostomy

RISC

RNA-induced silencing complex

RNA

Ribonucleic acid

sALS

Sporadic ALS

SCA2

Spinocerebellar Ataxia Type 2

siRNA

Small interfering RNA

SNP

Sniff nasal pressure

SOD1

Superoxide dismutase 1

TDP-43

Transactive response DNA binding protein 43 kDa

VC

Vital capacity

Not applicable.

Not applicable.

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166. Zancanella V., van Rooijen K., van Vliet R., Pereira I., de Ruiter A., Shtefaniuk V., Kieper S., Wartel M., Dobrynin G., Kovačević J., et al. AAV-miQURE®-mediated targeting of hexanucleotide repeat expansion-containing transcripts in ALS C9orf72 mouse models. Hum. Gene Ther. 2022;33:A72-A73. [Google Scholar]

Data Availability Statement

No new experimental data were created or analyzed in this study. Data sharing is not applicable to this article.

Articles from Cells are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

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Current State and Future Directions in the Therapy of ALS

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying ...

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ALS is caused by the degeneration of motor neurons in the motor cortex, spinal cord, and brainstem. When neurons are lost, they are replaced by scar tissue (gliosis) and spinal cord and muscles shrink (atrophy). Special markers of ALS include Bunina bodies in nerve cells as well as abnormal buildup of TDP-43 protein. This leads to muscle weakness.

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Continuing Education Activity

Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig's disease," is a neurodegenerative disease of the motor neurons. This activity reviews the etiology and evaluation of amyotrophic lateral sclerosis (ALS). In addition, it outlines the treatments and interventions available. This activity highlights the role of the interprofessional healthcare team in evaluating and treating patients with this condition.

Objectives:

Summarize the etiology of ALS.

Outline the typical findings on the examination of a patient with ALS.

Describe the interventions available for patients with ALS.

Review the importance of collaboration and communication among the interprofessional team to enhance the coordination of care for patients affected by ALS.

Access free multiple choice questions on this topic.
Introduction

Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig disease," is a neurodegenerative disease of the motor neurons. No single etiology has been proven; rather, multiple pathways (both heritable and sporadic) have been shown to result in unmistakably similar disease entities. ALS necessarily affects both upper and lower motor neurons with variable patterns of onset, most commonly beginning with signs of lower motor neuron degeneration within proximal limbs. As it is a progressive disease, it will eventually lead to paralysis and, inevitably, death. There is no cure for ALS; however, multiple medications and interventions can reduce symptoms and prolong life, sometimes up to 10 or more years.

Etiology

Although many potential mechanisms have been proposed, a precise, single etiology of sporadic amyotrophic lateral sclerosis is yet unproven. These mechanisms include altered RNA processing leading to prion-like self-aggregation, superoxide dismutase type 1 SOD1 mutations leading to free radical toxicity, cascading inflammatory responses, and excessive concentrations of glutamate, among others.[1][2] The rarer entity of familial ALS has numerous genetic mechanisms, most frequently repeat expansion of the C9ORF72 gene and various mutations of the SOD1 gene.[3] Mutated SOD1 protein misfolds and forms aggregates, leading to cellular injury and eventually apoptosis. Both genetic aberrations are inherited in a mainly autosomal dominant pattern.[4] Ultimately, rather than a single unifying cause, ALS is an etiologically diverse clinical entity, which is the result of a multitude of separate potential preceding aberrations.[5]

Epidemiology

Of the two forms of amyotrophic lateral sclerosis, 90-95% of cases are sporadic, with the remainder being familial. Within the United States, the prevalence of the disease is estimated at 5.2 per 100,000.[6] Worldwide incidence is approximately 1.6 cases per 100,000 persons annually, with similar rates demonstrated within the United States.[7][8] For sporadic ALS, male-to-female incidence ratios ranging from 1.3 to 1.5 have been demonstrated. Increased incidence is also noted with increases in age, particularly after 40 years of age.[9] Globally, a higher incidence is associated with White ethnicity.[10][11] The only established risk factors for ALS are age and family history; however, a growing body of evidence suggests cigarette smoking may also be a risk factor.[12]

Pathophysiology

The pathology of amyotrophic lateral sclerosis is characterized by the degeneration and gliosis of axons within the anterior and lateral columns of the spinal cord. Motor neurons within the spinal cord anterior horns and Betz cells within the motor cortex are also lost.[13] Unique to amyotrophic lateral sclerosis, Bunina bodies are eosinophilic inclusions visible in affected motor cells in many cases.[14] Intracellular TDP-43 inclusions are present in most cases, providing a pathologic link between ALS and frontotemporal dementia (FTD), in which they are also found.[15]

History and Physical

The most distinctive feature of Amyotrophic lateral sclerosis is the coexistence of upper and lower motor neuron signs and symptoms. Upper motor neuron (UMN) findings include hyperreflexia and spasticity, lower motor neuron (LMN) findings include muscle atrophy and fasciculations. Weakness can be attributed to either UMN or LMN. There are different phenotypes that determine the pattern of the above-mentioned symptoms and signs, as well as having prognostic significance:

Limb onset ALS (LO) is the predominant type, presenting in 70% of patients.[16] LO ALS can be further classified as flail arm syndrome or brachial amyotrophic diplegia, which is characterized by LMN weakness and wasting. It usually starts proximally and often symmetrically, then progresses distally to a point where upper extremity function is severely impaired.[17] LO ALS can also be classified as flail leg syndrome or pseudopolyneuritic variant, which is also characterized by LMN weakness and wasting, but of the lower extremities and with distal onset. Patients have a slower rate of progression to the involvement of other body segments and respiratory muscle weakness.[18]

Bulbar onset ALS accounts for 25% of patients and is characterized by UMN and LMN involvement of the cranial nerves, usually manifesting as speech difficulties and dysphagia followed by limb involvement in later stages.[16]

Although debated, some experts believe progressive muscular atrophy (PMA) represents a form of ALS. The disease is progressive, initially exclusively involving the LMN. Many patients go on to develop clinical signs and symptoms of UMN disease, at which point it is called lower motor neuron-onset ALS. Interestingly, even in those patients who never show clinical evidence of UMN involvement, corticospinal tract involvement is detected at autopsy in up to 50% to 66% of patients with an antemortem diagnosis of PMA.[19]

Primary lateral sclerosis (PLS) is a disorder of initially exclusive UMN disease. These patients have slower progression, lacking weight loss, and LMN symptoms/signs in the first four years of the disease. Most will eventually develop them, however, and at this point is known as upper motor neuron-dominant ALS.[20] These patients have a better prognosis than typical patients with ALS but worse than patients with PLS.[21]

If there are any additional symptoms/signs besides LMN and UMN disease, such as dementia (mostly frontotemporal), extrapyramidal, autonomic dysfunction, ocular motility disturbance, and/or sensory loss, these patients are considered to have ALS-plus syndrome.[22]

FTD, in particular, has a significant coincidence with ALS, with approximately 15% of patients with ALS demonstrating criteria for FTD. Many patients (about 30% to 50%) diagnosed with ALS will go on to develop varying degrees of cognitive impairment. While not overt dementia, patients can experience changes related to executive function and fluency, as well as behavioral changes such as apathy and disinhibition.

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

Evaluation

A widely accepted set of clinical criteria for the reliable diagnosis of Amyotrophic lateral sclerosis is the revised El Escorial criteria. Most recently updated in 1998, the criteria involve both specific findings that must be present and others that must be absent. The diagnosis requires evidence of both upper and lower motor neuron degeneration, together with the progressive spread of symptoms or signs. Also, there can be no evidence (electrophysiological, pathological, or radiological) of other disease processes that may be causing the aforementioned signs and symptoms.[23] Examples of lower motor neuron signs include weakness, muscle atrophy, and fasciculation, while clonus and pathologic spread of reflexes are upper motor neuron signs.

Specifically, the revised El Escorial criteria state that the diagnosis of ALS requires the presence of:

Clinical, electrophysical, or neuropathologic evidence of lower motor neuron degeneration,

Clinical, electrophysical, or neuropathologic evidence of upper motor neuron degeneration,

Evidence of progressive spread of symptoms or signs within a region or to other regions,

Combined with the absence of:

Electrophysiological or pathological evidence of other disease processes that might explain the patient's motor neuron degeneration,

Neuroimaging evidence of other diseases that might explain the observed clinical and electrophysiological signs.

While the diagnosis of ALS has historically been primarily clinical, electrodiagnostic studies can further support the diagnosis if the clinical picture is unclear. Electromyography (EMG) is useful in detecting the findings of acute denervation (fibrillation and positive sharp waves), chronic denervation (long-duration, complex motor unit action potentials [MUAP]), and chronic reinnervation (large amplitude MUAP).[24] Nerve conduction studies will show normal sensory action potentials.

The Awaji criteria also include fasciculation potentials as evidence of acute denervation, along with the previously established electrodiagnostic signs, fibrillation, and sharp waves. In addition, electrodiagnostic evidence is considered of equal weight to clinical exam findings of lower motor neuron abnormality. These changes increase sensitivity while preserving specificity from the revised El Escorial criteria.[25]

Motor nerve action potential amplitudes may be low before weakness is clinically evident.[26] To be indicative of ALS, needle EMG must show signs of acute or chronic denervation in at least three spinal levels (bulbar, cervical, thoracic, and/or lumbosacral). If three spinal levels are not abnormal, acute or, chronic denervation needs to be evident in three extremities with the involvement of at least two muscles supplied by two different roots and two different nerves in each extremity.

The World Federation of Neurology (WFN) has also set forth categories that aid in the description of ALS. Although the verbiage would seem to imply degrees of certainty, these categories instead reflect the degree of clinical involvement evident at the time of an examination. They are as follows:

Clinically definite ALS: UMN and LMN signs in at least 3 body segments.

Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs.

Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by EMG in at least two limbs.

Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs.

Clinically suspected ALS: Pure LMN syndrome with other causes of LMN disease adequately excluded.

Neither the El Escorial nor the Awaji criteria include specific radiologic findings in their diagnostic models. Therefore, while the role of radiology in the evaluation of ALS is mainly the exclusion of other possible etiologies of a patient's clinical picture, a few subtle imaging findings have been associated with the upper motor disease found in ALS. Neuroimaging of ALS relies solely on magnetic resonance imaging (MRI). Studies have shown patients with ALS to demonstrate iron accumulation within the precentral gyrus.[27] As a result, on susceptibility-weighted imaging, the decreased signal is visible across the precentral gyrus, which is known as the "motor band sign."[28] On conventional MRI, decreased signal intensity within the motor cortex on T2 weighted images has been associated with ALS and may be used to support the diagnosis. In addition, well-defined lesions of increased signal intensity can be visible within the corticospinal tracts on T2WI.

Findings indicative of upper motor neuronal disease have also been elucidated utilizing advanced MRI techniques such as spectroscopy and diffusion tensor imaging (DTI).[29] MR spectroscopy can detect and quantify chemical concentrations, specifically of N-acetyl aspartate (NAA), choline, and creatine within imaged tissues. Multiple studies have demonstrated decreased absolute and relative quantities of NAA in patients with ALS.[30][31][30]

Once the diagnosis has been established, genetic testing is encouraged, particularly for the SOD1 and C9ORF72 genotypes, due to emerging genotype-specific therapies in clinical trials. For patients who have a family history of the autosomal dominant disease, genetic testing can be used both as a screening tool and to provide prognostic information. For patients who have a family history of unclear inheritance, genetic testing can be useful to elucidate reduced penetrance or when information about family members is limited.

Treatment / Management

Unfortunately, symptomatic management is the main treatment in patients with amyotrophic lateral sclerosis, and it is recommended that their care team be interprofessional, with caregivers from neurology, physical therapy, occupational therapy, respiratory therapy, dietary, social work and nursing.[32]

Patients with ALS commonly suffer from chronic respiratory failure due to weakness of the diaphragmatic and intercostal muscles. As this weakness is progressive, it is recommended to have an early, careful discussion regarding respiratory management and future options such as tracheostomy, chronic ventilatory support, and noninvasive positive pressure ventilation (NIV). This discussion should be continuous, as it is expected that patients will change their opinion during their disease. Noninvasive ventilation is considered when orthopnea, nocturnal hypoxia, or a forced vital capacity (FVC) <50% present. Invasive ventilation is considered when NIV is not tolerated, or when the patient remains hypoxic and/or hypercarbic despite NIV. It is also important to offer appropriate information about terminal stage ALS when dyspnea and nocturnal hypoventilation begin, or when vital capacity (VC)<50% of predicted values. Patients should be made aware of palliative options for symptom control like anxiolytics, opiates, and/or sedation, as fears of "choking to death" are common.[33] Patients usually become symptomatic when VC <50%. When VS reaches <25% to 30%, there is a high risk of respiratory failure or sudden death. Hypoxia and hypercarbia are late findings that physicians should not rely on to predict the need for respiratory support.[34]

Progressive weakening of the muscles of mastication and swallowing results in dysphagia, which should be managed initially with diet modifications. As weight loss (particularly within the first two years after diagnosis) is associated with worse prognosis, emphasis should be placed on the intake of calorically dense foods and supplemental nutritional beverages.[35] As the dysphagia worsens, the risks of aspiration and weight loss increase. Numerous studies have demonstrated the efficacy of enteral nutrition via percutaneous gastrostomy, and it should be considered in patients with impaired oral intake. However, as there is no significant evidence regarding the impact of gastrostomy tube (G-tube) placement on quality of life, it should be an individualized discussion and decision. If the patient decides to have a G-tube placed, it should be done before the VC becomes <50% predicted value to avoid increased morbidity with the procedure itself.[36]

As the disease progresses, there will be increased dysarthria and the eventual impossibility of communication. As this can be frustrating to patients, with limited benefits found in speech therapy, the patient should choose an appropriate alternative communication method (writing, alphabet boards, electronic assistive communication devices).[37]

Frequent and painful muscle spasms can be treated with mexiletine, which was well-tolerated and demonstrated good symptomatic response at a dose of 150 mg BID. in a small sample study.[38][39] Other options are levetiracetam and with less efficacy gabapentin, baclofen, and tizanidine.[40] The latter two of which have shown efficacy in the management of spasticity. When oral therapy is not effective or well-tolerated, botulinum toxin injections into the spastic muscles can be useful. As weakness and functional decline inevitably progress, patients should be provided 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.[33]

Sialorrhea is very common and can be treated with atropine (0.4 mg q4-6h), hyoscyamine, amitriptyline (10 to 150 mg QHS), glycopyrrolate (1 mg TID), botulinum toxin injections into salivary glands, and even low-dose radiation therapy in those with refractory symptoms.[32][41][32]

Pseudobulbar affect (episodes of uncontrollable laughter or crying) can affect up to 50% of patients with ALS, especially those with the bulbar form. In these patients, AVP-923 (dextromethorphan-quinidine 20mg/10mg) has proven to be effective in a multicenter, randomized, double-blind, controlled clinical trial.[42] Less rigorous evidence has supported the use of amitriptyline and fluvoxamine in smaller trials.

Riluzole (50mg bid) is thought to reduce glutamate-induced excitotoxicity and is the only drug that has proven improved overall survival (74% vs. 58% placebo at 12 months) and survival without tracheostomy (57% vs. 50% at 18 months) in two multicenter randomized trials done in the late 90s. Similar to these studies exclusion criteria, AAN guidelines recommended using it in patients with definite or probable ALS by El Escorial criteria in whom other causes of progressive muscle atrophy have been ruled out, symptoms have been present less than 5 years, VC >60% of predicted, and who do not have a tracheostomy. Expert opinion has also suggested a potential benefit in patients who do not meet these criteria, specifically limited to aspiration prevention. Since the original trials, multiple class I trials have shown a modest effect with prolonged survival of 2-3 months, and multiple other lower-class trials showed that riluzole might be associated with prolonged survival from 6 to even 21 months. Overall, it is considered a safe medication, and AAN guidelines recommend offering it to patients.[36] It is important to note that the elimination of riluzole will be affected by CYP1A2 inhibitors like caffeine and theophylline. Transaminase elevation is expected in about 50% of patients, and it is recommended to monitor transaminases monthly for the first three months and every three months afterward.

Edaravone is a free radical scavenger that is thought to reduce oxidative stress and has proven to be beneficial on a subset of patients with early-stage (less than two years of symptoms, independently living, VC >80% and scores of 2 or more in all items of ALSFRS-R) probable or definite ALS. One study showed approximately 33% slower functional decline in patients at 24 weeks follow up.[43] It has the limitation of being very expensive at around $146,000 per year and is administered in 60 mg daily infusions for 14 days followed by 14 days off for the first cycle, and then 60 mg/day for 10 days and 14 days off for the subsequent cycles. Edaravone should be used with caution in patients with asthma as it can cause serious asthmatic reactions in up to 5%.

Pain is a commonly reported symptom of patients with ALS, arising from numerous causes including muscle cramping, spasticity, and as a result of decreased mobility. Spasticity should be treated specifically, as outlined above. Assistive devices such as special mattresses, pillows, and wheelchairs may help to prevent pain. Ultimately many patients require nonopioid analgesics and anti-inflammatory drugs, and when these fail, opioids become the mainstay of pain treatment.[44]

Depression has a significant effect on the quality of life in patients with ALS, and studies have shown that treatment can improve quality of life. While no controlled trials have evaluated the treatment of depression in patients with ALS, Amitriptyline is commonly used as it can also treat other symptoms such as insomnia, sialorrhea, and pseudobulbar affect.

The issue of end-of-life care, and advanced directives, should be broached soon after diagnosis. One of the most important discussions revolves around tracheostomy placement and mechanical ventilation. Due to increased caregiver burden and significant associated costs, very few patients with ALS in the united states (less than 10%) opt for invasive ventilation. Hospice care can provide many resources that are not available, or as readily available in the home and can increase the likelihood of a peaceful death.[45] Dyspnea and anxiety are two common complaints that can be treated with morphine, and lorazepam or diazepam, respectively.

Differential Diagnosis

Multiple diseases can mimic amyotrophic lateral sclerosis including, but not limited to: cervical myelopathy, multifocal motor neuropathy, myasthenia gravis, Lambert-Eaton syndrome, inclusion body myositis, benign fasciculation, monomelic amyotrophy, spinal muscular atrophy, spinal bulbar muscular atrophy, poliomyelitis or post-poliomyelitis syndrome, late-onset Tay-Sachs disease, motor neuron syndromes secondary to lymphoproliferative disorders and other cancers, intraspinal lesions, radiation spinal myelopathy, hexosaminidase A deficiency, cramp-fasciculation syndrome, neuromyotonia, radiculoplexopathy, thyrotoxicosis, and myopathies.[46][47][48][49]

Prognosis

The median survival is of 3 to 5 years; however, around 30% of patients are alive after five years of diagnosis and 10% to 20% after ten years. Factors associated with better survival include increased weight at diagnosis (mild obesity by BMI), younger age at onset, higher ALS functional rating scale score, FVC at presentation, and limb rather than bulbar symptoms.[50][51]

Complications

As mentioned in the treatment and management section, there are numerous complications associated with amyotrophic lateral sclerosis, including respiratory decline with eventual need for ventilatory support, dysphagia, dysarthria, malnutrition, spasms, spasticity, fatigue, functional decline due to muscular weakness, sialorrhea, thick mucus secretions and pseudobulbar affect. In addition, some complications may arise due to the less-common medications meant to manage symptoms of the disease itself. These side effects include gastrointestinal upset and arrhythmias in mexiletine, transaminitis and asthenia in Riluzole, and gait disturbance and headache in edaravone.

Postoperative and Rehabilitation Care

Rehabilitation

Rehabilitating individuals with ALS requires an interdisciplinary approach to address the broad scope of therapeutic needs. Early intervention is crucial to maximize functional mobility and longevity. Comprehensive initial assessments of balance, gait, muscle strength and tone, activity tolerance, and performance of activities of daily living (ADLs) guide interventions targeting specific deficits. Fall prevention strategies (including assistive devices and environmental modifications) and energy conservation techniques are needed as the weakness and fatigue that comes with the progression of ALS increase the risk for falls and further injury in these patients. Orthoses and adaptive equipment may also be utilized for these patients to further their independence with ADLs.

Collaboration among healthcare providers, therapists, and caregivers is vital for comprehensive disease management. Throughout the course of care, it is important to not only be mindful of the trajectory of the disease but to focus on problem-solving and maximizing the patient's comfort, functionality, and quality of life.[52][53]

Deterrence and Patient Education

Patients need to know that this disease causes the muscles to weaken, eventually to the point of paralysis. Patients should also be aware that the disease will get worse and ultimately lead to death. Unfortunately, there is no cure; however, numerous medications can help lessen the associated symptoms. Patients may begin to notice difficulty with fine motor skills, from speaking to writing, as well as with walking, and eventually breathing.

Enhancing Healthcare Team Outcomes

ALS is a disease that necessarily progresses to significant, multifactorial debilitation and eventually death. As the clinical entity of ALS is broad in its subclassifications, involving many potential separate systems and symptoms, there is no single, standard model of patient care. Rather, the care plan of each patient needs to take into account the degree of lower motor involvement and weakness, especially whether it has progressed to the respiratory muscles, upper motor neuron involvement/spasticity, degrees of dysarthria and dysphagia, as well as the presence of other potentially associated symptoms such as frontotemporal dementia and depression. While the composition of these care teams will undoubtedly change based on the presence and degree of these symptoms, the interprofessional team will usually include the following practitioners: Physician, occupational and physical therapists, respiratory therapists, dietician, speech pathologist, social worker, and case manager. When patients with ALS are cared for by such an interprofessional team, there have been significant, demonstrable benefits in both the quality of life, as well as the length of survival.[54][55] [Level 2]

References

Disclosure: Ryan Brotman declares no relevant financial relationships with ineligible companies.

Disclosure: Maria Moreno-Escobar declares no relevant financial relationships with ineligible companies.

Disclosure: Joe Joseph declares no relevant financial relationships with ineligible companies.

Disclosure: Gauri Pawar declares no relevant financial relationships with ineligible companies.

# data[].attributes.attachment_link.description
Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig disease," is a neurodegenerative disease of the motor neurons. No single etiology has been proven; rather, multiple pathways (both heritable and sporadic) have been shown to result in unmistakably similar disease entities.

# data[].attributes.body
Genetics- (hereditary ALS) children with parents who have ALS have a 50% chance of inheriting the gene

Age- most common between ages 60-mid 80's; greater risk at greater age

Sex- slightly more men than women before the age of 65 develop ALS

Smoking- women who smoke are at higher risk for ALS

Environmental toxin exposure- no one agent has been proven to be associated with ALS, but evidence suggests that lead and other chemicals can be risk factors

Military service- it is not clear why people who serve in the military are at higher risk for developing ALS

# data[].attributes.attachment_link.readable_text
Overview

Amyotrophic lateral sclerosis (a-my-o-TROE-fik LAT-ur-ul skluh-ROE-sis), known as ALS, is a nervous system disease that affects nerve cells in the brain and spinal cord. ALS causes loss of muscle control. The disease gets worse over time.

ALS is often called Lou Gehrig's disease after the baseball player who was diagnosed with it. The exact cause of the disease is still not known. A small number of cases are inherited.

ALS often begins with muscle twitching and weakness in an arm or leg, trouble swallowing or slurred speech. Eventually ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for this fatal disease.

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Symptoms

Symptoms of ALS vary from person to person. Symptoms depend on which nerve cells are affected. ALS generally begins with muscle weakness that spreads and gets worse over time. Symptoms might include:

Trouble walking or doing usual daily activities.

Tripping and falling.

Weakness in the legs, feet or ankles.

Hand weakness or clumsiness.

Slurred speech or trouble swallowing.

Weakness associated with muscle cramps and twitching in the arms, shoulders and tongue.

Untimely crying, laughing or yawning.

Thinking or behavioral changes.

ALS often starts in the hands, feet, arms or legs. Then it spreads to other parts of the body. Muscles get weaker as more nerve cells die. This eventually affects chewing, swallowing, speaking and breathing.

There's generally no pain in the early stages of ALS. Pain also is not common in the later stages. ALS doesn't usually affect bladder control. It also usually doesn't affect the senses, including the ability to taste, smell, touch and hear.

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Causes

ALS affects the nerve cells that control voluntary muscle movements such as walking and talking. These nerve cells are called motor neurons. There are two groups of motor neurons. The first group extends from the brain to the spinal cord to muscles throughout the body. They're referred to as upper motor neurons. The second group extends from the spinal cord to muscles throughout the body. They're referred to as lower motor neurons.

ALS causes both groups of motor neurons to gradually deteriorate and then die. When motor neurons are damaged, they stop sending messages to the muscles. As a result, the muscles can't function.

For about 10% of people with ALS, a genetic cause can be identified. For the rest, the cause is not known.

Researchers continue to study possible causes of ALS. Most theories center on a complex interaction between genes and factors in the environment.

Risk factors

Established risk factors for ALS include:

Genetics. For about 10% of people with ALS, a risk gene was passed down from a family member. This is called hereditary ALS. In most people with hereditary ALS, their children have a 50% chance of inheriting the gene.

Age. Risk increases with age up to age 75. ALS is most common between the ages of 60 and the mid-80s.

Sex. Before the age of 65, slightly more men than women develop ALS. This sex difference disappears after age 70.

Environmental factors, such as the following, have been associated with an increased risk of ALS.

Smoking. Evidence supports that smoking is an environmental risk factor for ALS. Women who smoke seem to be at even higher risk, particularly after menopause.

Environmental toxin exposure. Some evidence suggests that exposure to lead or other substances in the workplace or at home might be linked to ALS. Much study has been done, but no one agent or chemical has been consistently associated with ALS.

Military service. Studies indicate that people who have served in the military are at higher risk of ALS. It's not clear what about military service might trigger ALS. It might include exposure to certain metals or chemicals, traumatic injuries, viral infections, or intense exertion.

Complications

As the disease progresses, ALS causes complications, such as:

Breathing problems

Over time, ALS leads to weakness of the muscles used to breathe. People with ALS might need a device such as a mask ventilator to help them breathe at night. The device is similar to what someone with sleep apnea might wear. This type of device supports the person's breathing through a mask worn over the nose, the mouth or both.

Some people with advanced ALS choose to have a tracheostomy. This is a surgically created hole at the front of the neck leading to the windpipe. A ventilator may work better on a tracheostomy than on a mask.

The most common cause of death for people with ALS is breathing failure. Half of people with ALS die within 14 to 18 months of diagnosis. However, some people with ALS live 10 years or longer.

Speaking problems

Most people with ALS develop weakness of the muscles used to form speech. This usually starts with slower speech and occasional slurring of words. It then becomes harder to speak clearly. This can progress to the point that others can't understand the person's speech. Other forms of communication and technology are used to communicate.

Eating problems

People with ALS can develop weakness of the muscles involved with swallowing. This can lead to malnutrition and dehydration. They are also at higher risk of getting food, liquids or saliva into the lungs, which can cause pneumonia. A feeding tube can reduce these risks and ensure proper hydration and nutrition.

Dementia

Some people with ALS have problems with language and decision-making. Some are eventually diagnosed with a form of dementia called frontotemporal dementia.

Show references

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22. Soga T, et al. Long-term outcomes after surgery to prevent aspiration for patients with amyotrophic lateral sclerosis. BMC Neurology. 2022; doi:10.1186/s12883-022-02619-z.

23. Rutkove SB, et al. Differential diagnosis of peripheral nerve and muscle disease. https://www.uptodate.com/contents/search. Accessed March 9, 2023.

24. National Amyotrophic Lateral Sclerosis (ALS) Registry. Centers for Disease Control and Prevention. https://www.cdc.gov/als/GeneralPublic_AboutRegistry.html. Accessed March 9, 2023.

25. Johnson SA (expert opinion). Mayo Clinic. March 8, 2023.

26. Staff NP (expert opinion). Mayo Clinic. March 9, 2023.

27. Oskarsson BE (expert opinion). Mayo Clinic. Feb. 21, 2023.

# data[].attributes.attachment_link.title
Amyotrophic lateral sclerosis (ALS) - Symptoms and causes

# data[].attributes.attachment_link.description
This progressive nervous system disease, also known as Lou Gehrig's disease, destroys nerve cells.

# data[].attributes.body
AlS is developed from a mix of genetic mutation and molecular problems causing damage to motor neurons. When nerve cells (astrocytes) fail to clear glutamate, it builds up and overstimulates the neurons causing excitotoxicity. This leads to an overload of calcium and cell death. Gene mutations like TDP-43 disrupt the way RNA is processed. This increases oxidative stress, causes protein clumps, damages the mitochondria and blocks axonal transport. Inflammatory chemicals are released by overactive microglia and make nerve damage a lot worse.

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Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and…

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There are over 120 genes linked to ALS

Common ones include:

C9ORF72

TDP-43

FUS

SOD1

Environmental Risks include:

concussions

military service

smoking

heavy metals

pesticides/toxins

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Continuing Education Activity

Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig's disease," is a neurodegenerative disease of the motor neurons. This activity reviews the etiology and evaluation of amyotrophic lateral sclerosis (ALS). In addition, it outlines the treatments and interventions available. This activity highlights the role of the interprofessional healthcare team in evaluating and treating patients with this condition.

Objectives:

Summarize the etiology of ALS.

Outline the typical findings on the examination of a patient with ALS.

Describe the interventions available for patients with ALS.

Review the importance of collaboration and communication among the interprofessional team to enhance the coordination of care for patients affected by ALS.

Access free multiple choice questions on this topic.
Introduction

Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig disease," is a neurodegenerative disease of the motor neurons. No single etiology has been proven; rather, multiple pathways (both heritable and sporadic) have been shown to result in unmistakably similar disease entities. ALS necessarily affects both upper and lower motor neurons with variable patterns of onset, most commonly beginning with signs of lower motor neuron degeneration within proximal limbs. As it is a progressive disease, it will eventually lead to paralysis and, inevitably, death. There is no cure for ALS; however, multiple medications and interventions can reduce symptoms and prolong life, sometimes up to 10 or more years.

Etiology

Although many potential mechanisms have been proposed, a precise, single etiology of sporadic amyotrophic lateral sclerosis is yet unproven. These mechanisms include altered RNA processing leading to prion-like self-aggregation, superoxide dismutase type 1 SOD1 mutations leading to free radical toxicity, cascading inflammatory responses, and excessive concentrations of glutamate, among others.[1][2] The rarer entity of familial ALS has numerous genetic mechanisms, most frequently repeat expansion of the C9ORF72 gene and various mutations of the SOD1 gene.[3] Mutated SOD1 protein misfolds and forms aggregates, leading to cellular injury and eventually apoptosis. Both genetic aberrations are inherited in a mainly autosomal dominant pattern.[4] Ultimately, rather than a single unifying cause, ALS is an etiologically diverse clinical entity, which is the result of a multitude of separate potential preceding aberrations.[5]

Epidemiology

Of the two forms of amyotrophic lateral sclerosis, 90-95% of cases are sporadic, with the remainder being familial. Within the United States, the prevalence of the disease is estimated at 5.2 per 100,000.[6] Worldwide incidence is approximately 1.6 cases per 100,000 persons annually, with similar rates demonstrated within the United States.[7][8] For sporadic ALS, male-to-female incidence ratios ranging from 1.3 to 1.5 have been demonstrated. Increased incidence is also noted with increases in age, particularly after 40 years of age.[9] Globally, a higher incidence is associated with White ethnicity.[10][11] The only established risk factors for ALS are age and family history; however, a growing body of evidence suggests cigarette smoking may also be a risk factor.[12]

Pathophysiology

The pathology of amyotrophic lateral sclerosis is characterized by the degeneration and gliosis of axons within the anterior and lateral columns of the spinal cord. Motor neurons within the spinal cord anterior horns and Betz cells within the motor cortex are also lost.[13] Unique to amyotrophic lateral sclerosis, Bunina bodies are eosinophilic inclusions visible in affected motor cells in many cases.[14] Intracellular TDP-43 inclusions are present in most cases, providing a pathologic link between ALS and frontotemporal dementia (FTD), in which they are also found.[15]

History and Physical

The most distinctive feature of Amyotrophic lateral sclerosis is the coexistence of upper and lower motor neuron signs and symptoms. Upper motor neuron (UMN) findings include hyperreflexia and spasticity, lower motor neuron (LMN) findings include muscle atrophy and fasciculations. Weakness can be attributed to either UMN or LMN. There are different phenotypes that determine the pattern of the above-mentioned symptoms and signs, as well as having prognostic significance:

Limb onset ALS (LO) is the predominant type, presenting in 70% of patients.[16] LO ALS can be further classified as flail arm syndrome or brachial amyotrophic diplegia, which is characterized by LMN weakness and wasting. It usually starts proximally and often symmetrically, then progresses distally to a point where upper extremity function is severely impaired.[17] LO ALS can also be classified as flail leg syndrome or pseudopolyneuritic variant, which is also characterized by LMN weakness and wasting, but of the lower extremities and with distal onset. Patients have a slower rate of progression to the involvement of other body segments and respiratory muscle weakness.[18]

Bulbar onset ALS accounts for 25% of patients and is characterized by UMN and LMN involvement of the cranial nerves, usually manifesting as speech difficulties and dysphagia followed by limb involvement in later stages.[16]

Although debated, some experts believe progressive muscular atrophy (PMA) represents a form of ALS. The disease is progressive, initially exclusively involving the LMN. Many patients go on to develop clinical signs and symptoms of UMN disease, at which point it is called lower motor neuron-onset ALS. Interestingly, even in those patients who never show clinical evidence of UMN involvement, corticospinal tract involvement is detected at autopsy in up to 50% to 66% of patients with an antemortem diagnosis of PMA.[19]

Primary lateral sclerosis (PLS) is a disorder of initially exclusive UMN disease. These patients have slower progression, lacking weight loss, and LMN symptoms/signs in the first four years of the disease. Most will eventually develop them, however, and at this point is known as upper motor neuron-dominant ALS.[20] These patients have a better prognosis than typical patients with ALS but worse than patients with PLS.[21]

If there are any additional symptoms/signs besides LMN and UMN disease, such as dementia (mostly frontotemporal), extrapyramidal, autonomic dysfunction, ocular motility disturbance, and/or sensory loss, these patients are considered to have ALS-plus syndrome.[22]

FTD, in particular, has a significant coincidence with ALS, with approximately 15% of patients with ALS demonstrating criteria for FTD. Many patients (about 30% to 50%) diagnosed with ALS will go on to develop varying degrees of cognitive impairment. While not overt dementia, patients can experience changes related to executive function and fluency, as well as behavioral changes such as apathy and disinhibition.

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

Evaluation

A widely accepted set of clinical criteria for the reliable diagnosis of Amyotrophic lateral sclerosis is the revised El Escorial criteria. Most recently updated in 1998, the criteria involve both specific findings that must be present and others that must be absent. The diagnosis requires evidence of both upper and lower motor neuron degeneration, together with the progressive spread of symptoms or signs. Also, there can be no evidence (electrophysiological, pathological, or radiological) of other disease processes that may be causing the aforementioned signs and symptoms.[23] Examples of lower motor neuron signs include weakness, muscle atrophy, and fasciculation, while clonus and pathologic spread of reflexes are upper motor neuron signs.

Specifically, the revised El Escorial criteria state that the diagnosis of ALS requires the presence of:

Clinical, electrophysical, or neuropathologic evidence of lower motor neuron degeneration,

Clinical, electrophysical, or neuropathologic evidence of upper motor neuron degeneration,

Evidence of progressive spread of symptoms or signs within a region or to other regions,

Combined with the absence of:

Electrophysiological or pathological evidence of other disease processes that might explain the patient's motor neuron degeneration,

Neuroimaging evidence of other diseases that might explain the observed clinical and electrophysiological signs.

While the diagnosis of ALS has historically been primarily clinical, electrodiagnostic studies can further support the diagnosis if the clinical picture is unclear. Electromyography (EMG) is useful in detecting the findings of acute denervation (fibrillation and positive sharp waves), chronic denervation (long-duration, complex motor unit action potentials [MUAP]), and chronic reinnervation (large amplitude MUAP).[24] Nerve conduction studies will show normal sensory action potentials.

The Awaji criteria also include fasciculation potentials as evidence of acute denervation, along with the previously established electrodiagnostic signs, fibrillation, and sharp waves. In addition, electrodiagnostic evidence is considered of equal weight to clinical exam findings of lower motor neuron abnormality. These changes increase sensitivity while preserving specificity from the revised El Escorial criteria.[25]

Motor nerve action potential amplitudes may be low before weakness is clinically evident.[26] To be indicative of ALS, needle EMG must show signs of acute or chronic denervation in at least three spinal levels (bulbar, cervical, thoracic, and/or lumbosacral). If three spinal levels are not abnormal, acute or, chronic denervation needs to be evident in three extremities with the involvement of at least two muscles supplied by two different roots and two different nerves in each extremity.

The World Federation of Neurology (WFN) has also set forth categories that aid in the description of ALS. Although the verbiage would seem to imply degrees of certainty, these categories instead reflect the degree of clinical involvement evident at the time of an examination. They are as follows:

Clinically definite ALS: UMN and LMN signs in at least 3 body segments.

Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs.

Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by EMG in at least two limbs.

Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs.

Clinically suspected ALS: Pure LMN syndrome with other causes of LMN disease adequately excluded.

Neither the El Escorial nor the Awaji criteria include specific radiologic findings in their diagnostic models. Therefore, while the role of radiology in the evaluation of ALS is mainly the exclusion of other possible etiologies of a patient's clinical picture, a few subtle imaging findings have been associated with the upper motor disease found in ALS. Neuroimaging of ALS relies solely on magnetic resonance imaging (MRI). Studies have shown patients with ALS to demonstrate iron accumulation within the precentral gyrus.[27] As a result, on susceptibility-weighted imaging, the decreased signal is visible across the precentral gyrus, which is known as the "motor band sign."[28] On conventional MRI, decreased signal intensity within the motor cortex on T2 weighted images has been associated with ALS and may be used to support the diagnosis. In addition, well-defined lesions of increased signal intensity can be visible within the corticospinal tracts on T2WI.

Findings indicative of upper motor neuronal disease have also been elucidated utilizing advanced MRI techniques such as spectroscopy and diffusion tensor imaging (DTI).[29] MR spectroscopy can detect and quantify chemical concentrations, specifically of N-acetyl aspartate (NAA), choline, and creatine within imaged tissues. Multiple studies have demonstrated decreased absolute and relative quantities of NAA in patients with ALS.[30][31][30]

Once the diagnosis has been established, genetic testing is encouraged, particularly for the SOD1 and C9ORF72 genotypes, due to emerging genotype-specific therapies in clinical trials. For patients who have a family history of the autosomal dominant disease, genetic testing can be used both as a screening tool and to provide prognostic information. For patients who have a family history of unclear inheritance, genetic testing can be useful to elucidate reduced penetrance or when information about family members is limited.

Treatment / Management

Unfortunately, symptomatic management is the main treatment in patients with amyotrophic lateral sclerosis, and it is recommended that their care team be interprofessional, with caregivers from neurology, physical therapy, occupational therapy, respiratory therapy, dietary, social work and nursing.[32]

Patients with ALS commonly suffer from chronic respiratory failure due to weakness of the diaphragmatic and intercostal muscles. As this weakness is progressive, it is recommended to have an early, careful discussion regarding respiratory management and future options such as tracheostomy, chronic ventilatory support, and noninvasive positive pressure ventilation (NIV). This discussion should be continuous, as it is expected that patients will change their opinion during their disease. Noninvasive ventilation is considered when orthopnea, nocturnal hypoxia, or a forced vital capacity (FVC) <50% present. Invasive ventilation is considered when NIV is not tolerated, or when the patient remains hypoxic and/or hypercarbic despite NIV. It is also important to offer appropriate information about terminal stage ALS when dyspnea and nocturnal hypoventilation begin, or when vital capacity (VC)<50% of predicted values. Patients should be made aware of palliative options for symptom control like anxiolytics, opiates, and/or sedation, as fears of "choking to death" are common.[33] Patients usually become symptomatic when VC <50%. When VS reaches <25% to 30%, there is a high risk of respiratory failure or sudden death. Hypoxia and hypercarbia are late findings that physicians should not rely on to predict the need for respiratory support.[34]

Progressive weakening of the muscles of mastication and swallowing results in dysphagia, which should be managed initially with diet modifications. As weight loss (particularly within the first two years after diagnosis) is associated with worse prognosis, emphasis should be placed on the intake of calorically dense foods and supplemental nutritional beverages.[35] As the dysphagia worsens, the risks of aspiration and weight loss increase. Numerous studies have demonstrated the efficacy of enteral nutrition via percutaneous gastrostomy, and it should be considered in patients with impaired oral intake. However, as there is no significant evidence regarding the impact of gastrostomy tube (G-tube) placement on quality of life, it should be an individualized discussion and decision. If the patient decides to have a G-tube placed, it should be done before the VC becomes <50% predicted value to avoid increased morbidity with the procedure itself.[36]

As the disease progresses, there will be increased dysarthria and the eventual impossibility of communication. As this can be frustrating to patients, with limited benefits found in speech therapy, the patient should choose an appropriate alternative communication method (writing, alphabet boards, electronic assistive communication devices).[37]

Frequent and painful muscle spasms can be treated with mexiletine, which was well-tolerated and demonstrated good symptomatic response at a dose of 150 mg BID. in a small sample study.[38][39] Other options are levetiracetam and with less efficacy gabapentin, baclofen, and tizanidine.[40] The latter two of which have shown efficacy in the management of spasticity. When oral therapy is not effective or well-tolerated, botulinum toxin injections into the spastic muscles can be useful. As weakness and functional decline inevitably progress, patients should be provided 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.[33]

Sialorrhea is very common and can be treated with atropine (0.4 mg q4-6h), hyoscyamine, amitriptyline (10 to 150 mg QHS), glycopyrrolate (1 mg TID), botulinum toxin injections into salivary glands, and even low-dose radiation therapy in those with refractory symptoms.[32][41][32]

Pseudobulbar affect (episodes of uncontrollable laughter or crying) can affect up to 50% of patients with ALS, especially those with the bulbar form. In these patients, AVP-923 (dextromethorphan-quinidine 20mg/10mg) has proven to be effective in a multicenter, randomized, double-blind, controlled clinical trial.[42] Less rigorous evidence has supported the use of amitriptyline and fluvoxamine in smaller trials.

Riluzole (50mg bid) is thought to reduce glutamate-induced excitotoxicity and is the only drug that has proven improved overall survival (74% vs. 58% placebo at 12 months) and survival without tracheostomy (57% vs. 50% at 18 months) in two multicenter randomized trials done in the late 90s. Similar to these studies exclusion criteria, AAN guidelines recommended using it in patients with definite or probable ALS by El Escorial criteria in whom other causes of progressive muscle atrophy have been ruled out, symptoms have been present less than 5 years, VC >60% of predicted, and who do not have a tracheostomy. Expert opinion has also suggested a potential benefit in patients who do not meet these criteria, specifically limited to aspiration prevention. Since the original trials, multiple class I trials have shown a modest effect with prolonged survival of 2-3 months, and multiple other lower-class trials showed that riluzole might be associated with prolonged survival from 6 to even 21 months. Overall, it is considered a safe medication, and AAN guidelines recommend offering it to patients.[36] It is important to note that the elimination of riluzole will be affected by CYP1A2 inhibitors like caffeine and theophylline. Transaminase elevation is expected in about 50% of patients, and it is recommended to monitor transaminases monthly for the first three months and every three months afterward.

Edaravone is a free radical scavenger that is thought to reduce oxidative stress and has proven to be beneficial on a subset of patients with early-stage (less than two years of symptoms, independently living, VC >80% and scores of 2 or more in all items of ALSFRS-R) probable or definite ALS. One study showed approximately 33% slower functional decline in patients at 24 weeks follow up.[43] It has the limitation of being very expensive at around $146,000 per year and is administered in 60 mg daily infusions for 14 days followed by 14 days off for the first cycle, and then 60 mg/day for 10 days and 14 days off for the subsequent cycles. Edaravone should be used with caution in patients with asthma as it can cause serious asthmatic reactions in up to 5%.

Pain is a commonly reported symptom of patients with ALS, arising from numerous causes including muscle cramping, spasticity, and as a result of decreased mobility. Spasticity should be treated specifically, as outlined above. Assistive devices such as special mattresses, pillows, and wheelchairs may help to prevent pain. Ultimately many patients require nonopioid analgesics and anti-inflammatory drugs, and when these fail, opioids become the mainstay of pain treatment.[44]

Depression has a significant effect on the quality of life in patients with ALS, and studies have shown that treatment can improve quality of life. While no controlled trials have evaluated the treatment of depression in patients with ALS, Amitriptyline is commonly used as it can also treat other symptoms such as insomnia, sialorrhea, and pseudobulbar affect.

The issue of end-of-life care, and advanced directives, should be broached soon after diagnosis. One of the most important discussions revolves around tracheostomy placement and mechanical ventilation. Due to increased caregiver burden and significant associated costs, very few patients with ALS in the united states (less than 10%) opt for invasive ventilation. Hospice care can provide many resources that are not available, or as readily available in the home and can increase the likelihood of a peaceful death.[45] Dyspnea and anxiety are two common complaints that can be treated with morphine, and lorazepam or diazepam, respectively.

Differential Diagnosis

Multiple diseases can mimic amyotrophic lateral sclerosis including, but not limited to: cervical myelopathy, multifocal motor neuropathy, myasthenia gravis, Lambert-Eaton syndrome, inclusion body myositis, benign fasciculation, monomelic amyotrophy, spinal muscular atrophy, spinal bulbar muscular atrophy, poliomyelitis or post-poliomyelitis syndrome, late-onset Tay-Sachs disease, motor neuron syndromes secondary to lymphoproliferative disorders and other cancers, intraspinal lesions, radiation spinal myelopathy, hexosaminidase A deficiency, cramp-fasciculation syndrome, neuromyotonia, radiculoplexopathy, thyrotoxicosis, and myopathies.[46][47][48][49]

Prognosis

The median survival is of 3 to 5 years; however, around 30% of patients are alive after five years of diagnosis and 10% to 20% after ten years. Factors associated with better survival include increased weight at diagnosis (mild obesity by BMI), younger age at onset, higher ALS functional rating scale score, FVC at presentation, and limb rather than bulbar symptoms.[50][51]

Complications

As mentioned in the treatment and management section, there are numerous complications associated with amyotrophic lateral sclerosis, including respiratory decline with eventual need for ventilatory support, dysphagia, dysarthria, malnutrition, spasms, spasticity, fatigue, functional decline due to muscular weakness, sialorrhea, thick mucus secretions and pseudobulbar affect. In addition, some complications may arise due to the less-common medications meant to manage symptoms of the disease itself. These side effects include gastrointestinal upset and arrhythmias in mexiletine, transaminitis and asthenia in Riluzole, and gait disturbance and headache in edaravone.

Postoperative and Rehabilitation Care

Rehabilitation

Rehabilitating individuals with ALS requires an interdisciplinary approach to address the broad scope of therapeutic needs. Early intervention is crucial to maximize functional mobility and longevity. Comprehensive initial assessments of balance, gait, muscle strength and tone, activity tolerance, and performance of activities of daily living (ADLs) guide interventions targeting specific deficits. Fall prevention strategies (including assistive devices and environmental modifications) and energy conservation techniques are needed as the weakness and fatigue that comes with the progression of ALS increase the risk for falls and further injury in these patients. Orthoses and adaptive equipment may also be utilized for these patients to further their independence with ADLs.

Collaboration among healthcare providers, therapists, and caregivers is vital for comprehensive disease management. Throughout the course of care, it is important to not only be mindful of the trajectory of the disease but to focus on problem-solving and maximizing the patient's comfort, functionality, and quality of life.[52][53]

Deterrence and Patient Education

Patients need to know that this disease causes the muscles to weaken, eventually to the point of paralysis. Patients should also be aware that the disease will get worse and ultimately lead to death. Unfortunately, there is no cure; however, numerous medications can help lessen the associated symptoms. Patients may begin to notice difficulty with fine motor skills, from speaking to writing, as well as with walking, and eventually breathing.

Enhancing Healthcare Team Outcomes

ALS is a disease that necessarily progresses to significant, multifactorial debilitation and eventually death. As the clinical entity of ALS is broad in its subclassifications, involving many potential separate systems and symptoms, there is no single, standard model of patient care. Rather, the care plan of each patient needs to take into account the degree of lower motor involvement and weakness, especially whether it has progressed to the respiratory muscles, upper motor neuron involvement/spasticity, degrees of dysarthria and dysphagia, as well as the presence of other potentially associated symptoms such as frontotemporal dementia and depression. While the composition of these care teams will undoubtedly change based on the presence and degree of these symptoms, the interprofessional team will usually include the following practitioners: Physician, occupational and physical therapists, respiratory therapists, dietician, speech pathologist, social worker, and case manager. When patients with ALS are cared for by such an interprofessional team, there have been significant, demonstrable benefits in both the quality of life, as well as the length of survival.[54][55] [Level 2]

References

Disclosure: Ryan Brotman declares no relevant financial relationships with ineligible companies.

Disclosure: Maria Moreno-Escobar declares no relevant financial relationships with ineligible companies.

Disclosure: Joe Joseph declares no relevant financial relationships with ineligible companies.

Disclosure: Gauri Pawar declares no relevant financial relationships with ineligible companies.

# data[].attributes.attachment_link.description
Amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig disease," is a neurodegenerative disease of the motor neurons. No single etiology has been proven; rather, multiple pathways (both heritable and sporadic) have been shown to result in unmistakably similar disease entities.

# data[].attributes.body
Descriptive symptoms and diagnosis for ALS

# data[].attributes.attachment_link.description
The initial symptoms of ALS can be quite varied in different people. One person may have trouble grasping a pen or lifting a coffee cup, while another person may experience a change in vocal pitch when speaking.

# data[].attributes.body
progression rate can vary

mean survival rate is 2-5 years

trouble with fine motor skills (grasping pen, lifting cup)

progressive muscle weakness (painless, initial sign)

weakness in hands, arms, legs, feet, speech or swallowing muscles)

tripping or dropping things

abnormal fatigue

muscle cramps and twitching

paralysis develops as disease progresses

respiratory muscle weakness

# data[].attributes.attachment_link.description
The initial symptoms of ALS can be quite varied in different people. One person may have trouble grasping a pen or lifting a coffee cup, while another person may experience a change in vocal pitch when speaking.

# data[].attributes.body
difficulty walking

hand weakness or clumsiness

slurred speech, trouble swallowing

emotional changes, untimely crying or laughing

often starts in hands feet arms or legs

little or no pain in early and late stages

taste, smell, touch, and hearing generally unaffected

# data[].attributes.attachment_link.readable_text
Overview

Amyotrophic lateral sclerosis (a-my-o-TROE-fik LAT-ur-ul skluh-ROE-sis), known as ALS, is a nervous system disease that affects nerve cells in the brain and spinal cord. ALS causes loss of muscle control. The disease gets worse over time.

ALS is often called Lou Gehrig's disease after the baseball player who was diagnosed with it. The exact cause of the disease is still not known. A small number of cases are inherited.

ALS often begins with muscle twitching and weakness in an arm or leg, trouble swallowing or slurred speech. Eventually ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for this fatal disease.

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Symptoms

Symptoms of ALS vary from person to person. Symptoms depend on which nerve cells are affected. ALS generally begins with muscle weakness that spreads and gets worse over time. Symptoms might include:

Trouble walking or doing usual daily activities.

Tripping and falling.

Weakness in the legs, feet or ankles.

Hand weakness or clumsiness.

Slurred speech or trouble swallowing.

Weakness associated with muscle cramps and twitching in the arms, shoulders and tongue.

Untimely crying, laughing or yawning.

Thinking or behavioral changes.

ALS often starts in the hands, feet, arms or legs. Then it spreads to other parts of the body. Muscles get weaker as more nerve cells die. This eventually affects chewing, swallowing, speaking and breathing.

There's generally no pain in the early stages of ALS. Pain also is not common in the later stages. ALS doesn't usually affect bladder control. It also usually doesn't affect the senses, including the ability to taste, smell, touch and hear.

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Causes

ALS affects the nerve cells that control voluntary muscle movements such as walking and talking. These nerve cells are called motor neurons. There are two groups of motor neurons. The first group extends from the brain to the spinal cord to muscles throughout the body. They're referred to as upper motor neurons. The second group extends from the spinal cord to muscles throughout the body. They're referred to as lower motor neurons.

ALS causes both groups of motor neurons to gradually deteriorate and then die. When motor neurons are damaged, they stop sending messages to the muscles. As a result, the muscles can't function.

For about 10% of people with ALS, a genetic cause can be identified. For the rest, the cause is not known.

Researchers continue to study possible causes of ALS. Most theories center on a complex interaction between genes and factors in the environment.

Risk factors

Established risk factors for ALS include:

Genetics. For about 10% of people with ALS, a risk gene was passed down from a family member. This is called hereditary ALS. In most people with hereditary ALS, their children have a 50% chance of inheriting the gene.

Age. Risk increases with age up to age 75. ALS is most common between the ages of 60 and the mid-80s.

Sex. Before the age of 65, slightly more men than women develop ALS. This sex difference disappears after age 70.

Environmental factors, such as the following, have been associated with an increased risk of ALS.

Smoking. Evidence supports that smoking is an environmental risk factor for ALS. Women who smoke seem to be at even higher risk, particularly after menopause.

Environmental toxin exposure. Some evidence suggests that exposure to lead or other substances in the workplace or at home might be linked to ALS. Much study has been done, but no one agent or chemical has been consistently associated with ALS.

Military service. Studies indicate that people who have served in the military are at higher risk of ALS. It's not clear what about military service might trigger ALS. It might include exposure to certain metals or chemicals, traumatic injuries, viral infections, or intense exertion.

Complications

As the disease progresses, ALS causes complications, such as:

Breathing problems

Over time, ALS leads to weakness of the muscles used to breathe. People with ALS might need a device such as a mask ventilator to help them breathe at night. The device is similar to what someone with sleep apnea might wear. This type of device supports the person's breathing through a mask worn over the nose, the mouth or both.

Some people with advanced ALS choose to have a tracheostomy. This is a surgically created hole at the front of the neck leading to the windpipe. A ventilator may work better on a tracheostomy than on a mask.

The most common cause of death for people with ALS is breathing failure. Half of people with ALS die within 14 to 18 months of diagnosis. However, some people with ALS live 10 years or longer.

Speaking problems

Most people with ALS develop weakness of the muscles used to form speech. This usually starts with slower speech and occasional slurring of words. It then becomes harder to speak clearly. This can progress to the point that others can't understand the person's speech. Other forms of communication and technology are used to communicate.

Eating problems

People with ALS can develop weakness of the muscles involved with swallowing. This can lead to malnutrition and dehydration. They are also at higher risk of getting food, liquids or saliva into the lungs, which can cause pneumonia. A feeding tube can reduce these risks and ensure proper hydration and nutrition.

Dementia

Some people with ALS have problems with language and decision-making. Some are eventually diagnosed with a form of dementia called frontotemporal dementia.

Show references

1. Just what is ALS? ALS Association. https://www.als.org/understanding-als/what-is-als. Accessed Feb. 16, 2023.

2. Ferri FF. Amyotrophic lateral sclerosis. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Feb. 16, 2023.

3. Elman LB, et al. Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease. https://www.uptodate.com/contents/search. Accessed Feb. 16, 2023.

4. Preston DC, et al. Amyotrophic lateral sclerosis and its variants. In: Electromyography and Neuromuscular Disorders. 4th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Feb. 16, 2023.

5. Elman LB, et al. Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease. https://www.uptodate.com/contents/search. Accessed Feb. 16, 2023.

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# data[].attributes.attachment_link.title
Amyotrophic lateral sclerosis (ALS) - Symptoms and causes

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This progressive nervous system disease, also known as Lou Gehrig's disease, destroys nerve cells.

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ALS has no definitive test so diagnosis is based on clinical features and ruling out other diseases

Doctors look for:

upper motor neuron (UMN) signs (spasticity, brisk reflexes)

lower motor neuron (LMN) signs (muscle weakness, fasciculations)

Diagnostic criteria/tools

Awaji-shima criteria- improved sensitivity by treating EMG findings as LMN signs

Cortical hyperexcitability- early and specific biomarker of ALS

TMS tests- help distinguish ALS from lookalike neuromuscular disorders months earlier

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Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and…

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medications used for ALS

Qalsody- targets people with SOD1 gene delivered by Inthrathecal injection (lumbar puncture); slows ALS progression and improves symptoms

Radicava- delivered by IV infusion or oral suspension; slows physical decline

Nuedexta- delivered by capsule; treats involuntary laughing/crying and can improve speech and swallowing

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Studies all over the world, many funded by The ALS Association, are ongoing to develop more treatments and a cure for ALS. There are currently seven drugs approved by the U.S. Food and Drug Administration (FDA) to treat ALS and its symptoms: Qalsody, RELY

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Medical treatments:

Riluzole- survival benefit + 2-19 months

Edaravone(radicava)- slows decline

PB-TURSO- slows decline and increases survival by 6.5 months

Supportive and palliative care

PT- moderate exercise and stretching

OT- assisstive devices, ADL strategies

Speech therapy

high tech communication devices

Nutrition- high calorie increases survival

feeding support

ventilation - FVC,VC, SNP, nocturnal O2, blood gases

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Keywords: amyotrophic lateral sclerosis, ALS, motor neuron disease, MND, medication, therapy, supportive therapy, clinical trials, personalized medicine

2.1. Medical Treatment

2.1.1. Riluzole

For a long time, Riluzole (6-(trifluoromethoxy)-2-aminobenzothiazole) was the only treatment option available for patients with ALS. The targeted pathway was mainly aimed at the reduction of excitotoxicity, specifically the excitotoxicity of glutamate. The positive effect of Riluzole is thought to result from different actions. Firstly, its action as a sodium channel blocker on presynaptic neurons decreases glutamate release into the synaptic cleft. Furthermore, glutamate reuptake is increased through the activation of astrocytic excitatory amino acid transporter 2 (EAAT2) channels and, additionally, aminomethylphosphonic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors on postsynaptic neurons are inhibited noncompetitively. Lastly, gamma-aminobutyric acid (GABA) reuptake seems to be reduced and GABA receptors potentiated [ 27, 28, 29, 30, 31].

Riluzole was approved by the FDA in 1995 and subsequently the EMA in 1996. In the first study examining the treatment of ALS patients with Riluzole, 155 participants were included in a prospective, double-blind, placebo-controlled trial. The intervention group received a daily dose of 100 mg of Riluzole, the standard dosage still valid today. After a treatment period of one year, a significant delay of disease progression was shown [ 4]. A further multicenter double-blind and placebo-controlled study with 959 participants confirmed these results in 1996 [ 32], suggesting a survival benefit of two to three months in both studies. However, real-world analyses suggest a higher survival benefit, ranging up to 19 months [ 33]. Most importantly, the study was able to identify Riluzole as a generally well-tolerated drug and determined the side effects, including asthenia, nausea, gastrointestinal problems, as well as augmentation in hepatic enzymes.

The Riluzole drug was first developed as an oral tablet of 50 mg taken twice a day but given the fact that many ALS patients are struggling with dysphagia, the development of a bioequivalent oral suspension of Riluzole (5 mg/mL) was essential [ 34, 35]. Furthermore, recently, an oral-film formulation form of Riluzole has been developed that poses another option to simplify administration and ensure the continuation of medical treatment [ 36, 37].

2.1.2. Edaravone

After the approval of Riluzole, no new drug entered the market for years until, in 2015, Edaravone (3-methyl-1-phenyl-2-pyrazoline-5-one) was approved in Japan and South Korea. After its FDA approval in 2017, China's NMPA and Switzerland followed with admissions in 2019, Indonesia in 2020, and, finally, Malaysia and Thailand in 2021. Edaravone has been used in acute-phase stroke intervention in Japan for years [ 38] and was designed to reduce oxidative stress and neuroinflammatory response by scavenging free radicals [ 39, 40, 41]. Its use in ALS treatment is based on a randomized, double-blind, placebo-controlled phase III trial with 137 participants [ 42]. Inclusion criteria allowed only participants with early stage ALS defined as disease duration of two years or less, ALSFRS-R scores of at least two for every item of the ALSFRS-R, forced vital capacity (FVC) of 80% or more, as well as a probable or definite ALS diagnosis as defined by the revised El Escorial criteria [ 42]. Prior to that, a previous phase III trial had not shown any significant overall effect of this drug [ 5]. Significant treatment effects were only shown after post hoc subgroup analysis with the above-mentioned criteria for early disease, which were then used in the second phase III study [ 43]. Results from the second phase III trial were a 33% reduction of ALSFRS-R decline over the 24-week treatment period and significantly better scoring on the ALSAQ-40 (forty item ALS assessment questionnaire; quality of life assessment tool). However, further studies did not yield significant effects, again [ 44, 45]. Typical side effects of Edaravone treatment were bruising, gait disturbances, headaches, and skin conditions [ 5, 46, 47].

Up to date, Edavarone is applied intravenously at a dosage of 60 mg/day. While the first administration takes place over a period of 14 days, all following monthly cycles take place for ten days. However, the convenience of this therapy method is below the one of orally assumable medicine. In 2022, an oral suspension of 105 mg/day was approved by the FDA. Simultaneously, there is a phase III trial conducted by Ferrer (TRICALS) for evaluating the safety and potential efficacy of FNP122, another oral application form of Edaravone.

2.1.3. Sodium Phenylbutyrate and Taurursodiol

Most recently, Sodium Phenylbutyrate and Taurursodiol (also known as PB-TURSO or PB-TUDCA [tauroursodeoxycholic acid] (Sodium 4-pheylbutanoate and 2-[(3α, 7β-dihydroxy-24-oxo-5β-cholan-24-yl) amino] ethane sulfonicacid, dihydrate) have been released as a fixed-dose combination. This drug is currently approved by the FDA and in Canada and both substances were previously approved for medical use separately. While Sodium Phenylbutyrate can be used in the treatment of hyperammonemia due to urea-cycle disorders [ 48], Taurursodiol has its place in the treatment of chronic cholestatic liver disorders [ 49]. Both have been identified as inhibitors of neuronal apoptosis and their combined action is proposed to reduce neuronal cell death and oxidative stress by decreasing stress in the endoplasmic reticulum (ER) and mitochondrial dysfunction [ 50, 51, 52, 53]. FDA approval was then based on results from a phase II multicenter, randomized, double-blinded trial (CENTAUR) that tested the safety and efficacy of a fixed-dose combination in 137 participants [ 3, 54, 55]. The combination of both substances slowed down disease progression (measured by the ALSFRS-R) by about 25% compared to the placebo group, and initiation of PB-TURSO treatment at baseline resulted in prolonged median survival of about 6.5 months. A phase III trial for the fixed-dose combination is currently ongoing and the recruitment of 664 participants was completed in February 2023 ( NCT05021536). The most common adverse events during the phase II trial were diarrhea, abdominal pain, nausea, and upper-respiratory-tract infections. Gastrointestinal-related adverse reactions occurred more frequently during the first three weeks of treatment [ 3].

Sodium phenylbutyrate/Taurursodiol was designed as an oral suspension and produced as a powder mixed with room-temperature water. The correct dosage contains 3 g of sodium phenylbutyrate and 1 g of Taurursodiol; it is initially administered once a day for three weeks and then twice a day.

2.2. Supportive Therapy

Supportive and palliative care is highly important to patients but rarely focused on in research. Nonmotor symptoms involving neuropsychiatric, autonomic, gastrointestinal, and vascular systems affect between 5% and 80% of people with ALS [ 56]. Thus, symptomatic treatment forms an important part of therapy in ALS patients and must be adapted to the clinical course. This includes symptomatic medical treatment for certain symptoms such as mood disturbances, pain, and spasticity that are usually not specially approved for ALS ( Figure 1a). The combination of dextromethorphan hydrobromide (20 mg) and quinidine sulfate (10 mg) was FDA-approved for ALS in 2011 for symptoms of frontal disinhibition such as frequent, involuntary, and often sudden episodes of crying and/or laughing [ 57]. While physical, occupational, and speech therapy as well as robotic assistance can maintain patients' autonomy, nutrition and home ventilation therapy aim to conserve somatic wellbeing. Studies have shown that access to and care through a tertiary ALS center can be a positive predictor [ 58] and are associated with increased six-month survival as well as reduced time to noninvasive ventilation (NIV) and gastrostomy [ 59]. Counseling and palliative care need to be discussed ( Figure 1b). Access to palliative care can improve the quality of life of patients and primary caregivers [ 60]. End-of-life discussions are an important part of patient care, especially as there is evidence suggesting that these discussions are often conducted with delay [ 61, 62]. Psychotherapy can alleviate depression and anxiety as studies on palliative care suggest and should therefore be offered, but there are only a few ALS-specific studies on this topic [ 63, 64]. Physical and speech therapy, occupational therapy, and robotic help systems are only some ways to help maintain functionality and, therefore, patients' autonomy for as long as possible, increasing the perceived quality of life [ 16, 17, 18]. Meanwhile, nutritional therapy may help in maintaining body weight and avoiding excessive weight loss by changing the quality and quantity of calorie intake as well as the administration method [ 19, 20]. During the final disease phase, progressive respiratory failure is addressed by the implementation of noninvasive and invasive ventilation attempting to alleviate hypercapnic symptoms and, in some cases, prolong survival [ 21]. Until a satisfactory causative treatment is found, supportive therapy and efforts to improve symptomatic medication remain of the utmost importance during disease accompaniment.

Figure 1.

Schematic overview of supportive therapy for patients with ALS: Different aspects are highlighted: ( a) Symptomatic medical treatment, ( b) Counseling and palliative care, ( c) Mobility, ( d) Speech and swallowing, and ( e) Ventilation. Created by Meret Herdick with "BioRender.com".

2.2.1. Mobility

Physical and Occupational Therapy

An important part of supportive treatment for ALS patients is active and passive physical therapy ( Figure 1c). Moderate active physical therapy has been shown to have a positive impact on the stabilization and maintenance of physical activity and ALSFRS-R levels when compared to passive therapy [ 16, 65]. A frequently prescribed therapy in ALS patients, a combination of stretching and motion exercises, but also endurance and aerobic movement therapy, is considered to be safe to perform [ 66]. While no particular training has proven to be superior regarding results in functionality, respirational capacity, or overall survival, a combination of all of the above can have a positive effect on the perceived quality of life and reduce subjective fatigue [ 67].

As an extension of physiotherapy, positive psychological and physical effects have been reported for motor-assisted movement exercisers (MME). These devices are for patients with muscle stiffness or weakness and can be used for physical exercise in the domestic area. Reports have shown positive psychological and physical effects [ 68] and more than 50% of frequent MME users report increased general wellbeing and reduced feelings of muscle stiffness.

Occupational therapy generally focuses on daily function while assessing, for example, the necessity for assistive devices and developing status-adapted strategies for tasks of everyday life and energy conversion [ 69, 70, 71]. The benefit of occupational therapy in ALS has been shown in small-sample studies. Music therapy, for example, led to an improved quality of life [ 72] and a single-subject study showed marked improvements in quality of life when involving aquatic therapy [ 73].

Robotics

Developments of robotic assistance aim, among other things, to battle progressive mobility restrictions experienced during ALS patients' individual disease course ( Figure 1c). A questionnaire-based study found more than 70% of ALS patients to be in favor of establishing robotic technology [ 68]. The prospect of greater independence increased the number of patients interested in robotic assistance for simple tasks such as serving drinks or handling an electronic device patients preferred robotic over human assistance [ 68, 74]. Currently, there are robotic solutions supporting patient independence and autonomy in different areas.

Addressing decreased mobility of the upper limbs, there are single-task devices specialized in performing, for example, food intake (e.g., "My Spoon" or "Obi") [ 74]. Furthermore, robotic lightweight arms, either fixed to a stationary workstation or mounted to a wheelchair, allow more complex movements within a certain radius [ 75]. Beyond these, there are efforts to develop wearable robotics, assisting the patient's body movement by exoskeletal support. A recent study worked on a lightweight wearable robotic device for assisted shoulder movement of patients with ALS, in which the device was able to compensate for continuing physical deterioration in 2 of 10 evaluated participants for a period of six months [ 76].

Exoskeletal approaches to compensate for lower-limb weakness and the related immobility are, for now, not focused on in ALS cohorts. Based on a recent review of wearable robotic exoskeletons in patients with spinal cord injuries, there are remarkable technological challenges that might impede effective everyday use in ALS patients. For example, the mean wearing time of different exoskeletons was around 10 min, and data regarding long-term use beyond 24 weeks is missing [ 77]. Generally, control of exoskeleton robotic systems can be realized through position, force, and speed sensors, or by using electromyographic (EMG) or electroencephalographic (EEG) signals [ 78]. Electrical wheelchairs are established tools for mobility in patients with different neurological diseases and are known to increase the quality of life and comfort while decreasing pain in ALS patients [ 79, 80]. Addressing the topic of steering without the necessity of precise fine motor skills, electromyographic surface sensors applied to temporalis muscles as well as autonomous navigation have been tested successfully [ 81, 82, 83]. Furthermore, electric wheelchairs controlled via eye-tracking devices are being investigated and there are already commercially available products on the market [ 84, 85, 86, 87]. In patients with severe disability and limited motor function, electrically adjustable beds can help with changing posture, especially when coupled with an eye-tracking system such as the "Environment Control in Amyotrophic Lateral Sclerosis (ECO-ALS) System" [ 88].

The field of robotics is also highly interesting regarding the topic of bulbar symptoms. For patients with the beginning of impairment of speech and preserved ability to use a touchscreen communication device, early access has been shown to positively influence the quality of life and may be especially helpful in improving communication skills in advanced disease stages [ 89]. An increased quality of life can be observed in severely dys- or anarthric patients when enabled access to eye-tracking devices for communication purposes [ 17]. During the last years, research has further focused on brain-computer interfaces which work independently from the residual motor activity and record neuroelectric signals in the brain [ 90]. Though not in standard clinical use yet, the first successful demonstrations of home use have been described, mainly for communication [ 91, 92, 93, 94].

There are constant efforts for technological improvement in order to help preserve patients' independence; however, there are few studies objectifying the benefits and possible disadvantages of robotics. We found no study or clinical trial regarding a possible positive effect on disease progression and survival, even though one could hypothesize, that patients with access to robotics, for instance by using an electrical wheelchair with resulting passive joint movement, may have a survival benefit when compared to advanced-stage patients with impaired mobility or bed-bound patients. This fact should be taken into consideration for future studies, as technological improvement might help in maintaining autonomy.

2.2.2. Speech and Swallowing

Speech Therapy and Communication Devices

Most patients develop bulbar symptoms such as dysarthria and dysphagia during their individual disease course [ 95]. Speech therapy is not only a valuable therapeutic component of disease management but can be an effective method to screen for dysphagia as well ( Figure 1d) [ 95, 96, 97]. Therapists can help by teaching adaptive eating strategies and adjustment to communication devices in advanced dysarthria or anarthria. Unfortunately, studies evaluating the benefit of speech therapy in ALS, and progressively dysarthric patients in general, are rare. A British survey further elucidated the lack of validated treatment guidelines for speech therapists in progressive dysarthria [ 98]. The speech therapy's effect alone is smaller than the effects and benefits of communication devices themselves when looking at the quality of life in late dysarthria stages, indicating the importance of high-technology communication devices as a source for quality of life [ 99].

Nutritional Therapy

Numerous publications have discussed nutritional therapy and its impact on overall survival in ALS patients. While antioxidant or anti-inflammatory nutrients might be beneficial in nutritional therapy [ 100], most studies focus on weight or body mass index (BMI) loss as an adverse prognostic factor [ 101, 102]. Patients with ALS often show a decrease in body mass years before symptom onset [ 20] and weight loss from disease onset to diagnosis is associated with a reduced overall survival [ 103, 104]. Not only do patients struggle with reduced oral caloric intake due to dysphagia but are frequently affected by hypermetabolism, intestinal problems due to medication intake, and loss of appetite [ 105, 106]. Thus, malnutrition and underweight can be caused by a combination of several factors, all leading to higher morbidity and mortality.

While patients presenting a bulbar phenotype are more often affected by dysphagia and, therefore, malnutrition and underweight, it has been observed that patients with a rapidly progressing spinal phenotype, but no signs of dysphagia, can suffer severe weight loss, a similarly poor prognosis and early need for ventilation [ 103]. Again, this fact highlights the complexity of weight decline in motor neuron diseases.

The ESPEN guidelines for neurological diseases, therefore, suggest a 3-monthly follow-up for nutritional status, BMI calculation and dysphagia screening [ 107]. Depending on the baseline BMI, weight gain (when BMI is <25 kg/m ²), maintenance of body weight (when BMI is between 25-35 kg/m ²), or weight loss (when BMI is >35 kg/m ²) are recommended. The calorie intake is suggested to be around 30 kcal/kg body weight and reduced to 25-30 kcal/kg when patients are ventilated noninvasively. In a randomized and double-blinded placebo-controlled study on the LIPCAL-ALS cohort published in 2020, a high-caloric fatty diet was examined for its effect on overall patient survival and also on vital capacity (VC), quality of life (Schedule for the Evaluation of Individual Quality of Life, SEIQoL), BMI, and appetite (Council on Nutrition Appetite Questionnaire, CNAQ) [ 20]. A significant increase in BMI, as well as an increased survival probability in a subgroup of fast-progressing patients (according to ALSFRS-R point-loss per month), could be objectified. It remains, however, a matter of discussion as to whether the fatty diet or the increased caloric intake is to be held responsible for this effect. Up to this day, there is no consensus on what kind of high-caloric nutritional therapy should be suggested in general.

As disease progress, bulbar symptoms, dysphagia, and general weakness for oral nutrition can worsened. In this case, initial support such as high caloric supplements, thickening of liquids and chaperoned swallowing training are not anymore able to compensate for weight loss or swallowing difficulties. Nutrition via a percutaneous gastrostomy (PEG), radiologically inserted gastrostomy (RIG), or nasogastric tube (NGT) must then be considered [ 19]. Given that ALS is a progressive disease and nasogastric feeding is associated with higher numbers of intervention failures, as well as a reduction of well-being resulting from, among other things, sensory irritations, NGT is primarily a bridging option until PEG or RIG are established [ 108, 109]. Nutrition via PEG is associated with prolonged survival; the timing of PEG insertion, however, remains a matter of discussion [ 110, 111]. Although clinical practice suggests insertion while predicted FVC is above 50%, Bond et al. have demonstrated a survival benefit for those with predicted FVC above 60% at tube placing time [ 110]. In addition, PEG insertion prior to significant weight loss has been associated with a prolonged tracheostomy-free survival [ 112]. However, there was no difference in disease duration between patients with different PEG placement timings according to their disease duration [ 110]. Interestingly, PEG feeding did not have a significant effect on patient mood measured by the clinical impression of mood [ 110].

2.2.3. Ventilation

Ventilation marks one of the basic therapeutic options in the symptomatic treatment of patients affected by ALS, especially during later disease stages ( Figure 1e). Most patients do not show respiratory symptoms upon diagnosis but develop diaphragm muscle wasting during the course of the disease [ 2]. The resulting hypercapnia can lead to sleep disorders with daytime sleepiness, fatigue, and severe impairment in quality of life [ 113, 114].

Parameters such as FVC, VC, peak cough flow, and, in patients with bulbar symptoms, sniff nasal pressure (SNP) are easily measured upon clinical visits. Additional blood-gas analyses or nocturnal measurements of oxygen saturation can be helpful for the decision-making and monitoring of implemented NIV therapy [ 19]. NIV initiation is recommended, according to the EFNS guidelines, when either clinical symptoms develop or FVC drops below 80% [ 19]. However, positive effects can be observed in asymptomatic patients not fulfilling these criteria, and cough-assisting devices helping bronchial clearance can maximize them [ 19, 113]. Certainly, given patient consent, the benefit of NIV therapy is undiscussed, considering prolonged survival rates in frequent users [ 21, 115, 116]. Increased survival time is strongly associated with the usage duration per day. One study found increased survival rates for patients with a minimum of four hours of NIV per day, when adjusted for confounding predictors of survival [ 117]. Apart from the known survival benefit, there is evidence for improved quality of life associated with NIV therapy [ 21, 118, 119].

There are remarkable regional differences concerning the rate of invasive ventilation implemented in ALS patients. While in most European countries invasive ventilation via tracheostomy is performed in about 10% of patients, studies from Asian countries often report over 20% [ 120]. Studies from different countries and continents consistently report prolonged survival in invasively ventilated patients and the effect is greater in younger patients, patients without signs of Frontotemporal Dementia (FTD), and spinal onset phenotypes [ 120, 121]. Unfortunately, few studies have been performed on the quality of life after tracheostomy in ALS, which might be impaired by the need for intensive 24-h care and the initial loss of vocal communication [ 121]. Due to the invasive nature of this ventilation method, it is important to discuss all potential risks and benefits with patients and their caregivers prior to tracheostomy [ 122]. The involvement of primary caregivers in invasive ventilation has been shown to be especially important [ 123].

3.1. Therapies Currently Being Tested

As various trials aiming for new drug validation are taking place at the moment, we attempt to highlight some of the latter, focusing on the different techniques and the targeted pathways [ 11, 15, 124]. In this review, ongoing trials are divided into four distinct groups: (1) development of small molecules, (2) gene-specific therapies, (3) monoclonal-antibody therapies, and (4) stem-cell therapies. The different targeted pathways and therapeutical approaches currently evaluated in clinical trials discussed in this review are resumed in Figure 2 and Figure 3 and listed in Table 1.

Figure 2.

Small molecules in phase II/III and III clinical trials, grouped by mode of action: ( a) Excitotoxicity, ( b) Oxidative, ER, and mitochondrial stress, ( c) Neuroinflammation, ( d) Autophagy and Proteostasis, ( e) Neuronal death, muscle denervation and weakness, and ( f) Bioenergetic metabolism. ER: Endoplasmic reticulum. Created by Laura Tzeplaeff with "BioRender.com".

Figure 3.

Gene, antibody, and stem-cell therapeutic approaches: ( a) Antisense oligonucleotides, ( b) Viral vectors delivering RNA interference or CRISPER/Cas9, ( c) Monoclonal antibody, and ( d) Stem cell transplantation. ANTX2: Ataxin-2; BM-MSC: bone-marrow-derived mesenchymal stem cells; C9orf72: Chromosome 9 open reading frame 72; FUS: Fused in sarcoma; SOD1: Superoxide dismutase 1. Created by Laura Tzeplaeff with "BioRender.com".

3.1.1. Small Molecules

There are numerous ongoing studies regarding small molecule development, with a high number of them undergoing clinical phase III trials [ 15, 124]. In this part, we will mainly focus on molecules tested in phase II/III and in phase III clinical trials to examine drugs closest to possible approval. Each of these small molecules has a direct influence on several dysregulated pathways associated with ALS. Amongst them are glutamate excitotoxicity, oxidative stress, inflammation, autophagy, and metabolism, as well as neuronal death and muscle denervation and weakness. In order to give a short overview, we tried to group molecules according to the pathway they are the most closely related to ( Figure 2).

Excitotoxicity

As mentioned above ( Section 2.1.1), a main mechanism in treatment with Riluzole is targeting excitotoxicity, especially of glutamate. Apart from that, other phase III clinical trials are also aiming to reduce excitotoxicity in ALS ( Figure 2a). For example, cannabinoids have been shown to decrease spasticity, and are therefore used as symptomatic treatment in ALS [ 125]. Based on their protective effect on oxidative cell damage and excitotoxicity, MediCabilis CBD Oil ( NCT03690791) was tested in a single-center phase III clinical trial in a small sample of participants in Australia to further evaluate a possible disease-modifying effect [ 126, 127]. Furthermore, Memantine ( NCT04302870), a noncompetitive NMDA receptor antagonist used in the management of Alzheimer's disease, is currently being tested in a phase II/III clinical trial in the multiarm MND-SMART trial to help reduce excitotoxicity [ 128].

Oxidative Stress

Edaravone and Sodium Phenylbutyrate/Taurusodiol are, as mentioned before ( Section 2.1.2 and Section 2.1.3), mainly associated with the reduction of oxidative stress.

Currently, four other drugs with this mechanism are being tested in phase III clinical trials ( Figure 2b). Trazodone, an approved drug for the treatment of depression, is tested in a phase II/III trial as part of the multiarm MND-SMART trial mentioned above ( NCT04302870) [ 128]. This drug inhibits protein kinase ribonucleic acid (RNA)-like ER kinase (PERK) and reduces the formation of stress granules [ 128]. In cellular and ALS animal models, the inhibition of PERK showed a reduction of TDP-43 (transactive response DNA-binding protein 43 kDa) toxicity, and Trazodone was associated with a decreased production of toxic proteins [ 129, 130]. Furthermore, Pridopidine is a Sigma-1 receptor agonist that increases brain-derived neurotrophic factor secretion and is suggested to enhance axonal transport and promote neuronal survival in a superoxide dismutase 1 (SOD1) mouse model [ 131]. Pridopidine ( NCT04615923) is investigated as part of the phase II/III multiregimen HEALEY ALS platform trial ( NCT04297683). Deferiprone ( NCT03293069), also tested in a phase II/III clinical trial, is a chelator and, therefore, is able to reduce iron accumulation and the related excessive oxidative stress in motor pathways [ 132]. Huolingshengji granules ( NCT04950933), currently in a clinical phase II/III trial, are a traditional Chinese herbal medicine formula that consists of six herbs that demonstrate reduction of oxidative stress in ALS cell and mouse models [ 133, 134].

Neuroinflammation

Among the drugs in clinical phase III targeting neuroinflammation, we can count six different trials ( Figure 2c). Some trials were recently stopped in phase II/III due to their lack of benefit in ALS patients. Zilucoplan ( NCT04436497), stopped in mid of June 2020, and Ravulizumab ( NCT04248465), stopped in January 2023, are both inhibitors of complement component C5, a part of the immune-response pathways. One might conclude that C5 is not to be a plausible target in ALS. However, neuroinflammation as a target for new molecules includes studies on Triumeq ( NCT05193994) as well. It is a repurposed drug combination of dolutegravir, abacavir, and lamivudine, used in HIV treatment and chosen for its anti-inflammatory and anti-HERV (human endogenous retroviruses) antiviral qualities, which are currently being tested in an Australian ALS multicenter phase III trial [ 135]. MN-166 (Ibudilast, phase IIb/III trial) ( NCT04057898) is a small molecule with the ability to inhibit proinflammatory cytokines in activated glial cells and several other mechanisms targeting neuroinflammation [ 136]. MN-166 is further believed to enhance autophagosomal synthesis and autophagosome-lysosome fusion, as shown in a cellular study [ 137]. Masitinib ( NCT03127267), a tyrosine kinase inhibitor targeting, in part, mast cells and microglial cells, aims to reduce neuroinflammation and modulate the neuronal microenvironment in both the central and peripheral nervous systems [ 138, 139]. Masitinib is currently tested in a confirmatory phase III trial ( NCT03127267) in a group of early disease stage patients with moderate functional impairment at baseline and is expected to have the greatest treatment effect in this group, as previously established from a phase III trial with broader inclusion criteria [ 138, 139]. The phase II/III multiregimen HEALEY ALS Platform Trial also evaluates Verdiperstat ( NCT04436510), a molecule that inhibits myeloperoxidase. In the literature, inhibition of myeloperoxidase results in reduced motor impairment and microglia activation, decreasing neuroinflammation in a mouse model [ 140]. According to the observation of post mortem human brain tissues, this drug could have a greater effect on patients with SOD1 mutation [ 141].

Others

Apart from excitotoxicity, oxidative stress, and neuroinflammation, other ALS-linked disease mechanisms have been targeted in clinical trials. Boosting autophagy and direct action on protein aggregation are some of the paths pursued in alternative approaches. Arimoclomol ( NCT03836716), a drug that increases heat shock protein production and enhances autophagy, did not meet its primary or secondary endpoints of impact on function or survival, and the corresponding trial was terminated in July 2021. For now, not much is known about the results of this terminated study. Hopefully, the planned publication will allow insight into potential improvements and changes in future clinical trials targeting autophagy. Parallelly, other clinical trials targeting autophagy are still ongoing and look promising. Amongst those, Trehalose ( NCT05136885), a disaccharide, is currently being tested as part of the HEALEY ALS Platform Trial in a phase II/III trial in the USA [ 142, 143]. It is capable of enhancing autophagy and decreasing SOD1 mutant aggregates in mice.

One phase III trial is currently testing a fast skeletal muscle troponin activator, Reldesemtiv ( NCT04944784). This drug is a small molecule designed to slow the release of calcium during muscle contraction, improving muscle function and movement. In phase IIb, a benefit for Reldesemtiv could be demonstrated over time, when measuring the revised ALS functional rating scale (ALSFRS-R) and the slow vital capacity, especially at the study endpoint of 12 weeks. The authors postulate that the magnitude of the effect of Reldesemtiv could be even greater after a longer period of treatment [ 144]. However, this trial has been discontinued on 31 March 2023 due to futility, as no further evidence of positive effect had been observed on the primary and secondary endpoint after 24 weeks in patients treated with Reldesemtiv when compared to placebo-treated patients.

Methylcobalamin ( NCT03548311), a form of vitamin B12, when used in an ultrahigh dosage, was found to reduce denervation and reduce muscle weakness in a mouse model [ 39]. The results of the clinical phase III trial demonstrate similar positive results in humans with a slower functional decline in patients with early-stage ALS and having a moderate progression rate [ 145].

Insulin-like growth factor-1 ( NCT00035815) is a neurotrophic factor essential for the nervous system's development and can, as shown in animal models and cell culture systems, have a protective effect on neuronal cells [ 146, 147, 148, 149]. This effect is, supposedly, due to the blockage of cell-death pathways and promotion of muscle reinnervation as well as axonal growth and regeneration. However, results from a two-year phase III study concluded no benefit for ALS patients concerning survival time or muscle weakness [ 150]. To note, this study did not investigate the effect of IGF-1 on subgroups of patients concerning, for example, familial SOD1 mutations. Indeed, to our knowledge, the positive effect of IGF-1 was not investigated in any other model than SOD1 mouse models [ 146, 147, 148, 149].

CNM-Au8 ( NCT04615923) is another drug investigated as part of the phase II/III multiregimen HEALEY ALS Platform Trial. This molecule is a gold nanocrystal acting on energy metabolism and was developed by Clene Nanomedicine. This drug catalyzes the oxidation of NADH into NAD+ and increases the production of ATP to reduce oxidative stress in a mouse model [ 151].

To conclude the part on small molecules, there are many more clinical trials currently ongoing, either in phase II or I, and not detailed in here but nicely described in other recent reviews [ 11, 15, 124]. There are high expectations from current trials of small molecules, particularly for phase II/III trials approaching several new molecules at the same time. Examples are the multiregimen HEALEY ALS Platform Trial (estimated completion date: April 2026) or the multiarm MND-SMART (estimated completion date: December 2026) trial.

3.1.2. Gene-Specific Therapies

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are single-stranded synthetic oligonucleotides that can be designed to complement specific mRNAs and induce their degradation. ASOs have caused widespread media attention, with the FDA approval of Nusinersen and Eteplirsen in 2016 for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy that revolutionized the treatment of these two diseases [ 152, 153]. Thus, ASOs can be a powerful treatment approach in single-gene mutation diseases and could also be beneficial in ALS patients with specific gene mutation ( Figure 3a) [ 154]. The first phase III trial further elucidating ASOs in ALS with SOD1 mutation examined Tofersen ( NCT02623699; BIIB067), a drug applied intrathecally. Based on promising subgroup analyses from phase I and II trials, the VALOR (Part C) trial was performed [ 155]. While the ALSFRS-R levels in ALS patients did not differ significantly between the trial and placebo groups after 28 weeks, SOD1-levels in cerebrospinal fluid (CSF) and neurofilament light chain (NfL) levels in plasma lowered significantly [ 156]. Adverse events were most often related to lumbar puncture [ 156]. Of note, in this study, participants receiving Tofersen during earlier disease stages showed a smaller decline in ALSFRS-R score than those that had started Tofersen during the open-label extension phase. Based on this observation, participants are monitored in a long-term evaluation trial with expected completion in July 2024 ( NCT03070119). A study analyzing the effects of Tofersen in presymptomatic genetic SOD1 mutation carriers has been launched (ATLAS; NCT04856982) and expanded access programs enable global access for eligible patients ( NCT04972487). To note, the ALS population with mutant SOD1 represents 15-20% of fALS and approximately 3% of sALS. Thus, this strategy could be beneficial to a significant part of the ALS population and represents a big step forward in ALS therapy.

Developed for patients with fused in sarcoma ( FUS) gene mutations, ION363 is currently undergoing a phase III trial as well. The drug is applied intrathecally [ 157]. Autopsy results of the first application in a human suggested reduced FUS pathology due to the treatment [ 157]. Several other patients have therefore been treated in the expanded access program. The ongoing phase III trial (FUSION; NCT04768972), a placebo-controlled trial with a 2:1 ratio of investigational medical products to placebo, includes a "rescue" option that allows moving participants into the open-label extension phase in case of significant functional decline during the placebo-controlled study-observation period.

Further treatments that involve ASOs are currently being tested but have not reached phase III yet. A phase I clinical trial on IIB078, an ASO targeting C9orf72 (chromosome 9 open reading frame 72), has been stopped due to its lack of efficiency and reported worsening of symptoms in C9orf72 ALS patients (NCT03626012B). While SOD1 and FUS ALS patients, respectively, demonstrate an abnormally high amount of SOD1 and FUS protein, C9orf72-ALS patients, in contrast, demonstrate haploinsufficiency. In C9orf72-ALS patients, the RNA production from the C9orf72 gene, not the protein itself, is toxic [ 158, 159]. Thus, reduction of the C9orf72 protein with ASO might not work for this subgroup of ALS patients. However, another ongoing phase I/II clinical trial has been initiated on WVE-004, using a different ASO technology. For this trial, the ASO is targeting transcriptional variants containing hexanucleotide repeat expansion without affecting the protein level of C9orf72 ( NCT04931862). BIIB105 is being tested in a phase I trial for participants with Ataxin-2 (ATXN2) repeat expansion ( NCT04494256). ATXN2 is usually associated with Spinocerebellar Ataxia Type 2 (SCA2), causing the disease by an expansion of CAG triplets above a length of 22-23 repeats [ 160]. While repeat expansions above 35 are associated with full penetrance for SCA2, Elden et al. discussed an association of intermediate lengths of 27-33 repeats with ALS [ 160, 161]. Targeting ATXN2 induces the reduction of TDP-43 and showed improved motor function and survival in mouse models, which is why BIIB105 could be beneficial for both patients with and without Ataxin mutations, lowering the TDP-43 protein level [ 162].

Viral Vectors Delivering RNA Interference and CRISPR/Cas9

Viral vectors, for example, nonpathogenic adeno-associated viruses (AAVs), have the ability to transport exogenous molecules into cells. This mechanism can be used to deliver therapeutic agents into cells of the central nervous system (CNS). In contrast to therapeutic approaches based on ASOs, micro-RNA- or CRISPR/Cas9-containing vectors would only be injected once [ 163].

RNA interference is a biological mechanism initiated by the presence of short double-strand RNA (dsRNAs). Once dsRNAs are detected, they are degraded into micro-RNA (miRNA) or small interfering RNA (siRNA) and incorporated into the RNA-induced silencing complex (RISC). This RISC complex can then degrade the complementary mRNAs of the microRNA and thus prevent protein translation. Recent therapies design specific miRNAs to prevent the translation of ALS-linked proteins ( Figure 3b). For example, APB-102 (also named AMT-162) a SOD1 microRNA, delivered in AAVs and applied via intrathecal injection, was tested in two human patients [ 164]. Once incorporated into nervous cells, APB-102 targets and binds SOD1 mRNA, subsequently reducing its protein production. Not only the misfolded mutant SOD1 but also the misfolded wtSOD1 accumulate and aggregate in both familial ALS (fALS) and sporadic ALS (sALS) [ 165]. Thus, by reducing global SOD1, APB-102 may slow down ALS progression by reducing aggregation, improving the survival and function of motor neurons, and potentially providing a new therapeutic opportunity for ALS patients with SOD1 pathology. This approach could potentially give results similar to treatment with ASO against SOD1. However, the benefit of this approach is its convenience, avoiding readministration by performing a single injection. UniQure is currently acquiring the rights to develop this technique for phase I/II clinical trials, which is expected for the second half of 2023. Meanwhile, the company is also developing similar techniques to treat ALS patients with C9orf72 mutations using AMT-161 miRNA molecules. However, not much is known about this future product, and regarding the negative and detrimental result obtained with ASO treatment against C9orf72, we might expect an identical outcome when targeting global C9orf72 production. In 2022, at the 29th European Society of Gene and Cell Therapy (ESGCT) Congress, UniQure also presented AAV-miQURE ® results in an ALS C9orf72 mouse model [ 166]. This strategy selectively binds the mutant repeat expansion of C9orf72 mRNA, leading to the degradation of the toxic target transcripts without affecting native C9orf72 mRNA and protein. Up to now, this technique looks like a much more promising therapy.

Furthermore, viral vectors can also carry the CRISPR/Cas9 technology [ 167]. This gene-editing method is associated with a design RNA guide that enables the Cas9 endonuclease to cut at a desired genomic location and remove and/or add new genetic sections. The technique is not yet used in clinical trials; however, studies aiming to target SOD1 and C9orf72 pathogenic alleles on cell and animal models have been initiated [ 168, 169, 170].

In summary, ASO, RNAi, and CRISPR/Cas9 represent three different approaches to targeted gene therapy, offering opportunities for drug development for ALS patients with genetic mutations. AAV vectors can be used to mediate other gene delivery, for example, genes essential for neurotrophic support, or for modulating the neuromuscular junction. Thus, gene therapy is not necessarily limited to fALS but is also investigated for sALS, as reviewed by Amado et al., 2021 [ 163].

3.1.3. Monoclonal Antibodies

While there are no current phase III trials examining antibody treatment in ALS, there are interesting ongoing and completed phase II studies ( Figure 3c). Amongst those, one study is testing the human monoclonal antibody AL001 ( NCT05053035) in C9orf72-associated amyotrophic lateral sclerosis. AL001 binds the sortilin receptor and increases progranulin protein (PGRN) levels in C9orf72 ALS patients. In ALS mice models, progranulin demonstrates reduced TDP43 aggregation [ 171]. Furthermore, there is an ongoing phase III trial investigating AL001 in participants with heterozygous GRN (progranulin gene) mutations (INFRONT-3; NCT04374136), a causative mutation for FTD that is, in some cases, associated with ALS-FTD or pure ALS, as well [ 172, 173].

AP-101 ( NCT05039099), a human IgG1 antibody with high affinity and selective binding to misfolded SOD1 protein, is tested in a phase II trial on participants with both fALS and sALS, based on promising results from mouse models [ 174]. Further monoclonal antibodies are tested in phase II trials, aiming to reduce neuroinflammation (ANX005- NCT04569435, AT-1501- NCT04322149, Tocilizumab- NCT02469896). Further information is reviewed in Johnson et al., 2022, or Jiang et al., 2022 [ 15, 124].

3.1.4. Stem Cells

Stem cells, cells that-when guided into the desired direction by growth factors-can develop into any specific cell type, could function as a therapeutic approach in ALS. By developing into functioning neurons, these cells could replace damaged or apoptotic neurons. When injecting mesenchymal stem cells, the immune system could be guided towards an anti-inflammatory, neuroprotective environment by releasing different favorable soluble factors, instead of reacting to oxidative stress or degeneration by forming a proinflammatory, in parts toxic environment. There are different types of stem cells in use in preclinical and clinical trials. The most common among them are hematopoietic or mononuclear cells, neural stem cells, induced pluripotent stem cells, and mesenchymal stem cells. The latter is the most frequently investigated stem-cell type in human trials [ 175]. While preclinical studies showed positive effects in rodent models, mostly in presymptomatic animals, a gap for translation to an efficient trial culture in humans is yet to be filled [ 175]. While transient positive effects on clinical disease progression can be observed, patients demonstrated worsening in their respiratory function. Methodological challenges include (1) adequately big trial cohorts, (2) heterogeneity of eligible patient cohorts concerning their clinical and personal characteristics, (3) lack of placebo-controlled studies, and (4) the lack of publication of previously performed stem-cell trials [ 175]. There is a distinct need for large multicenter and placebo-controlled trials. Two studies on bone-marrow-derived mesenchymal stem cells (BM-MSC) are found in advanced trial stages in the context of ALS ( Figure 3d). NurOwn ® is available in an expanded-access protocol for patients who were enrolled in the preceding phase III trial. While the clinical endpoint was not met in the phase III trial, subgroup analyses of patients in early disease stages (ALSFS-R ≥ 35) as well as improvements of biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were promising ( NCT04681118) [ 176]. Lenzumestrocel (Neuronata-R ® Inj) ( NCT04745299), a BM-MSC as well, is currently being tested in a phase III clinical trial with an estimated enrolment of 115 participants, based on significant therapeutic benefits lasting at least six months in patients with ALS reported in the phase II trial ( NCT01363401) [ 177]. Beyond these, there are several other neuronal, monoclonal, and mesenchymal stem cell therapeutic strategies that are currently undergoing a phase I/II clinical trial [ 15, 124].

In conclusion, stem cells are an established treatment method in some hematological diseases, however, with numerous treatment-related risks. Results from the two ongoing phase III clinical trials will broaden knowledge of stem cells as a treatment option for ALS. However, the general challenges in trial culture, as discussed above, will have to be addressed before considering stem cells as a viable treatment option for ALS.

Table 1.

Approved Drug

Pathway

Phase

Therapeutic being tested (selection)

Pathway/Approach

Phase

3.2. Novel Therapeutic Approaches (Unaddressed or Poorly Addressed Yet)

We previously discussed the different clinical trials including molecules or techniques targeting certain ALS pathways. However, some ALS-dysregulated pathways are still unaddressed. In this section we will highlight different unaddressed mechanisms, amongst them post-translational modification (PTM), axonal transport, and others, discussing their potential benefit for future ALS treatment. These pathways are represented in green in Figure 4.

Figure 4.

Future strategies and approaches: ( a) Post-translational modification, ( b) Axonal transport, ( c) Nucleocytoplasmic transport, ( d) DNA damage, and ( e) Molecular tweezer. DNMTs: DNA methyltransferases; HDACi: histone deacetylase inhibitors; PARP: Poly ADP-ribose polymerase. Created by Laura Tzeplaeff with "BioRender.com".

3.2.1. Post-Translational Modification

Post-translational modifications (PTMs) impact proteins involved in the neuropathology of ALS, including FUS, SOD1, and TDP-43 [ 178, 179, 180]. Changes in acetylation, methylation, or phosphorylation are known to influence not only protein function but also their subcellular locations, interaction with other proteins or RNA, liquid-liquid phase separation, stress granule formation, cell death, as well as other processes [ 180, 181, 182, 183, 184]. A few strategies to target post-translational modification can be cited ( Figure 4 a).

Epigenetic mechanisms, including DNA methylation and histone modifications, are part of these PTMs and function as a key process in gene transcription regulation and DNA damage repair [ 185, 186, 187, 188, 189]. Recent studies have reported several dysregulations in histone PTMs in numerous ALS models, including alterations in acetylation, methylation, and phosphorylation, as well as global changes in epigenetic enzyme modifiers [ 190, 191, 192]. In order to revert these disease-associated alterations, most studies focus on the use of histone deacetylase inhibitors (HDACi) [ 193]. For example, the HDAC6 inhibitor is able to restore axonal transport and metabolic-lipidomic functions in ALS-FUS and ALS-TDP43 iPSC (induced pluripotent stem cells)-derived motor neurons [ 194, 195, 196, 197]. However, delivery to target and drug tolerance of HDACi are still improvable, as some show cytotoxic effects, depending on the cell type [ 198]. Interestingly, sodium phenylbutyrate, an HDACi, was recently approved by the FDA in combination with Taurursodiol, although the underlying mechanism in this context remains unclear [ 3]. Other studies report promising results when targeting protein and histone phosphorylation with commercially available kinase inhibitors, improving TDP43 localization and aggregation [ 182, 192, 199, 200]. Fasudil, a kinase inhibitor, is currently being tested in a phase II clinical trial for ALS treatment ( NCT03792490). As observed in ALS mouse models, it was able to restore the phosphorylation levels of certain proteins associated with synaptic and neuroinflammatory functions [ 201, 202].

Hope et al. recently detected changes in DNA methylation patterns in blood samples of more than 6.000 ALS patients worldwide and observed, that Riluzole was not able to revert specific DNA methylation changes in an efficient manner [ 203]. Motor neurons in human ALS show a significant increase in so-called DNA methyltransferases (DNMTs), responsible for DNA methylation production, as well [ 204]. Thus, inhibition of aberrant DNA methylation is a new direction that could possibly become relevant for new therapies for ALS. Some of these DNMT inhibitors are resumed by Martin et al., 2013 [ 205].

3.2.2. Axonal Transport

Targeting axonal transport is not completely unaddressed in clinical trials. Pridopidine ( NCT04297683), demonstrating enhanced axonal transport in a SOD1 mouse model, is currently being tested in a phase II/III trial [ 131]. As previously described, HDAC6 inhibitors can restore axonal transport defects in patient-derived motor neurons with FUS or TDP43 mutations. They are also able to restore axonal ER transport in the iPSC FUS model and mitochondrial transport in both FUS and TDP43 iPSC models [ 194, 197]. Interestingly, these two studies also demonstrated that HDAC6 inhibitors restore several other pathways altered in ALS, amongst them metabolic-lipidomic functions, aggregation, and subcellular localization. Since axonal transport interacts with other pathogenic mechanisms, restoring the latter might have an overall positive effect on disease progression ( Figure 4b) [ 206].

3.2.3. Nucleocytoplasmic Transport

Nucleocytoplasmic transport is poorly addressed in clinical trials but widely altered in ALS [ 207]. Inhibition of nuclear export or enhancement of nuclear import could be strategies to restore nucleocytoplasmic function in ALS ( Figure 4c) [ 208, 209, 210, 211]. The only clinical trial examining nucleocytoplasmic transport, that we are aware of, was implemented by Biogen. Here, BIIB100, a nuclear-export inhibitor targeting XPO1 ( NCT03945279), was tested; however, its phase I trial was terminated in June 2021 without clear reason.

3.2.4. DNA Damage

While the evidence linking excessive DNA damage to ALS is increasing, clinical trials acting on this pathway are lacking [ 212]. Modulating, for instance, the Poly ADP-ribose polymerase PARP1, a protein predominantly triggered by DNA damage, could have a positive effect on the disease. Generally, PARPs are enzymes that catabolize NAD+ to sequentially add adenosine diphosphate (ADP)-ribose subunits onto target proteins. This generates polymers of poly (ADP-ribose) (PAR). Interestingly, increased PAR was observed in the motor neurons of an ALS spinal cord [ 213]. Inhibition of PARP via Veliparib, an FDA-approved drug, decreases TDP-43 aggregation in culture cells and reduces TDP-43-associated neuronal loss in rat spinal cord cultures [ 213]. Olaparib, another FDA-approved PARP inhibitor, demonstrated a reduction of PAR levels and rescued TDP-43-induced death in culture cells. There are other approved PARP inhibitors that could be tested in the context of ALS [ 214]. Apart from PARP inhibitors, Fasudil and Cannabidiol (CBD), both previously discussed, are able to reduce the expression of PARPs ( Figure 4d) [ 215, 216].

3.2.5. Molecular Tweezer

Currently, most of the strategies regarding the inhibition of protein aggregation rely on the use of monoclonal antibodies, as previously discussed with AL001 ( NCT05053035) and AP-101 ( NCT05039099) clinical trials. A new interesting approach might be the use of small molecules, called molecular tweezers, which help in preventing the aggregation of toxic proteins ( Figure 4e). Molecular tweezers are host molecules with open cavities capable of binding molecules. For example, the CLR01 molecular tweezer acts as a nano chaperone that transiently binds abnormal protein self-assembly at positively charged amino acid residues (primarily lysine and to a lower extent arginine) and inhibits aggregates of multiple disease-associated proteins [ 217]. Thus, molecular tweezers work as a tool to target the process of abnormal protein self-assembly itself rather than a particular protein. The molecular tweezer CLR01 is able to decrease SOD1 aggregation in vitro and in vivo in the SOD1 mouse model [ 218, 219]. Unfortunately, this strategy did not succeed in slowing down motor symptoms. In contrast, CLR01 inhibiting Tau aggregation was able to ameliorate muscle-strength deterioration and anxiety- and disinhibition-like behavior in an Alzheimer's disease mouse model [ 220]. To our knowledge, CLR01 has not been tested in other ALS models than SOD1. CLR01 action in SOD1 is mainly explained by binding to lysine residues, and results vary depending on the type of mutation [ 218]. Since CLR01 also acts through arginine binding, and that FUS contains different arginine-rich regions, it is then tempting to speculate that CLR01's impact on the FUS-ALS model might have a different outcome than the one observed in the SOD1-ALS model. Neither was CLR01 tested in the C9orf72 model to test its efficiency on PR (proline-arginine), or GR (glycine-arginine) dipeptide repeat aggregation.

4.1. Clinical Characteristics

As a first step towards personalized trial culture, future studies will benefit from analyzing results depending on ALS subgroups. Overlaps of ALS with other diseases such as FTD or parkinsonism offer further possibilities for stratification [ 2]; 30-50% of ALS patients develop behavioral impairment, or criteria for FTD which is associated with worsened disease progression and shorter lifespan [ 1, 223, 224]. The phenotype, as well as overlap syndromes, show remarkable differences in overall survival. The pure lower motor neuron phenotype, for instance, has a median survival more than three times longer than the bulbar phenotype [ 225]. Multiple studies have identified the clinical phenotype as an independent prognostic factor and some have, at least in parts, included the phenotype as a prognostic factor into their model for prognosis [ 226, 227, 228]. Previous clinical trials demonstrated differences in treatment effectiveness depending on clinical phenotypes defined by disease onset or progression rate [ 4, 20]. Future studies should consider stratifying groups by their phenotypic manifestation. This might enhance the prediction of clinical progression rate (fast vs. slow), possibly resulting in improved statistical power.

4.2. Genetic Classification

Another strategy for subgroup division is stratification according to genetic mutations (for example, see Section 3.1.2 on gene-specific therapies). Overall, there are more than 30 genes known to cause fALS. The most common mutations affect C9orf72, SOD1, FUS, and TDP-43, differing in both clinical manifestation as well as treatment response [ 229]. Currently, so-called sporadic cases are occasionally not admitted to genetic testing, even though an empty family history does not exclude genetic alterations [ 229]. Not only de novo mutations, but also incomplete penetrance and phenotypic variability, presymptomatic disease stages in relatives, or even earlier, non-ALS-related death of mutation carriers can cause a falsely negative family history [ 230]. Grassano et al. found genetic alterations in 21.5% of sALS cases in a cohort of 1043 ALS patients and a genetic diagnosis in almost 27% of all individuals after having performed whole-genome sequencing [ 231]. It seems desirable to offer genetic counseling and routine genetic testing to all ALS patients at the time of diagnosis. Importantly, the results of genetic testing may require long waiting times, delaying possible treatment. Acceleration of genetic testing should be focused upon. When genetic alterations are present, relatives at risk may be offered genetic counseling as well as predictive testing. Presymptomatic monitoring and treatment possibilities for asymptomatic carriers may offer hope for thus far clinically unaffected individuals (e.g., ATLAS study for presymptomatic SOD1-mutation carriers- NCT04856982) [ 232]. As it is often suggested that disease evolution is gradual, presymptomatic treatment may prolong time-to-symptom onset as well as overall survival [ 233]. Importantly, all findings gained through genetic testing require interpretation by experienced professionals, calling for close interdisciplinary cooperation between geneticists and neurologists as well as extensive genetic counseling prior to testing.

4.3. The Power of Biomarkers

While studies on biomarker discovery mainly aim to accelerate and improve ALS diagnostics, enhancements in this field may also help in the prognostic evaluation as well as treatment-response monitoring. ALS patients experience progressive functional decline and limitations. The window for therapeutic opportunities remains relatively small. Therefore, early diagnosis is the key to early access to treatment and interventions. Here, a disease-specific biomarker (or biomarker panel) with high sensitivity and specificity for ALS would revolutionize diagnosis. The use of biomarkers for diagnostic and prognostic purposes in ALS is widely discussed in the review, which resulted from the Second ALS Young Investigators Academy [ 234]. In this section, we mainly address biomarkers that could be useful for treatment monitoring and patient stratification. Thus far, neurofilaments (Nf), proteins that can be found in myelinated axons, have been a matter of discussion as a main biomarker in ALS. The most frequently used blood-based biomarker is NfL [ 235]. In the case of neuronal/axonal damage, NfL levels increase in both CSF and blood and are highly correlated [ 236, 237]. There are efforts to establish NfL for monitoring pharmacodynamic treatment effects as well as prognostic classification. High levels of NfL have negative prognostic connotations [ 238, 239]; however, NfL levels remain relatively stable after disease onset, complicating its use as a prognostic marker for individual disease course after onset [ 238, 240, 241, 242]. In the recent phase III Tofersen trial, the primary clinical endpoint represented by ALSFRS-R decline was not reached, while significantly reduced NfL levels were observed. Nevertheless, a reduction of NfL level could be a sign of deceleration of disease progression [ 156]. For prognostic purposes as well as treatment monitoring, a combination of NfL with miRNA-181 derived from blood samples showed promising results [ 243]. Another example is TDP-43, taken from peripheral blood, which was correlated with time of generalization from bulbar or spinal symptoms to both regions. CSF pTDP-43 levels correlate with ALSFRS-R [ 244]. Furthermore, regulatory T cells have been investigated as markers of immune dysregulation with an inverse correlation to disease progression in ALS [ 245, 246, 247]. It may be interesting to investigate the regulatory T cells reaction to specific ALS treatments. Neopterin, a marker of proinflammatory state immune response, as well as p75, a marker of microglia and macrophage activation, both taken from urine samples, could be correlated to disease progression [ 248, 249]. Both biomarkers are especially interesting, as urine sampling is noninvasive and therefore feasible even in advanced disease stages. Similarly, tear fluid can be sampled noninvasively and has been the subject of a recent trial with promising results [ 250]. However, more studies in larger cohorts and longitudinal subsets are necessary in order to evaluate the benefit for therapy monitoring through biomarkers.

AAVs

Adeno-associated viruses

ADP

Adenosine diphosphate

ALS

Amyotrophic Lateral Sclerosis

ALSFRS-R

Revised ALS Functional Rating Scale

AMPA

Aminomethylphosphonic acid

ASO

Antisense oligonucleotide

ATXN2

Ataxin-2

BMI

Body mass index

CBD

Cannabidiol

C9orf72

Chromosome 9 open reading frame 72

CNS

Central nervous system

CSF

Cerebrospinal fluid

DNMTs

DNA methyltransferases

dsRNAs

Double strand RNA

EAAT2

Excitatory amino acid transporter 2

EEG

Electroencephalographic

EMG

Electromyographic

ER

Endoplasmic reticulum

fALS

Familial ALS

FTD

Frontotemporal Dementia

FUS

Fused in sarcoma

FVC

Forced vital capacity

GABA

Gamma-aminobutyric acid

HDACi

Histone deacetylase inhibitors

iPSC

Induced pluripotent stem cells

miRNA

micro RNA

MME

motor-assisted movement exercisers

Nf

Neurofilaments

NfL

Neurofilament light chain

NGT

Nasogastric tube

NIV

Non-invasive ventilation

NMDA

N-methyl-D-aspartate

PAR

Poly Adenosine diphosphate (ADP)-ribose

PARP

Poly ADP-ribose polymerase

PEG

Percutaneous gastrostomy

PERK

Protein kinase Ribonucleic acid (RNA)-like endoplasmic reticulum kinase

PGRN

Progranulin

PTMs

Post-translational modifications

RIG

Radiologically inserted gastrostomy

RISC

RNA-induced silencing complex

RNA

Ribonucleic acid

sALS

Sporadic ALS

SCA2

Spinocerebellar Ataxia Type 2

siRNA

Small interfering RNA

SNP

Sniff nasal pressure

SOD1

Superoxide dismutase 1

TDP-43

Transactive response DNA binding protein 43 kDa

VC

Vital capacity

Not applicable.

Not applicable.

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Data Availability Statement

No new experimental data were created or analyzed in this study. Data sharing is not applicable to this article.

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Current State and Future Directions in the Therapy of ALS

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying ...