ALS: Diagnosis by Deduction

In February 2019, Nancine M–a fifty-five-year-old woman with no history of asthma–had a breathing “episode.” She found it difficult to inhale. Eventually, she went into the hospital where they ran some tests, gave her oxygen, and sent her home with inhalers and an asthma diagnosis. That summer, Nancine went in for further breathing tests which determined that she was not suffering from asthma. Nancine had a new diagnosis: lung disease. After more tests, her doctors ruled out lung disease and told her it was an unusual type of asthma. However, they were not certain about the asthma diagnosis, so the doctors conducted more tests. During this time, Nancine lost some mobility in her left arm but didn’t mention it because it seemed unrelated to her breathing issues. 

When she finally mentioned her loss of mobility, her doctor sent her to a neurologist, who proceeded to send Nancine to a “specialist for nerve tests''. The clinic called to confirm her appointment, at which point Nancine found out that it was an ALS (amyotrophic lateral sclerosis) clinic. At her appointment in January 2020, Nancine had her fourth CT scan in six months and several blood tests. In February 2020–a year after her initial breathing difficulty–she was diagnosed with ALS. On the 26th of February 2021–one year and one week after her diagnosis–Nancine passed away at home next to her loving son. With improved diagnostic tools, Nancine’s doctors could have diagnosed her with ALS sooner which would have kept more treatment options open, potentially prolonging her life [1, 2]. 

Amyotrophic Lateral Sclerosis

You may have heard of ALS from the “Ice Bucket Challenge” which exploded on the internet in the summer of 2014. ALS is more commonly known as Lou Gehrig’s Disease–after the famous baseball player who was diagnosed with ALS in 1939. Like Alzheimer's disease and Parkinson’s, ALS is a neurodegenerative disorder, meaning that the nervous system is progressively damaged. ALS causes the deterioration of upper and lower motor neurons, the cells responsible for relaying instructions from the brain to the muscles.  Upper motor neurons are located in the brain and spinal cord while lower motor neurons extend from the spinal cord to the muscles in our body [2].

There are two primary types of ALS onset named for the location of initial symptoms: bulbar onset–referring to the brainstem–and spinal onset.  Nancine suffered from bulbar onset, which involves early symptoms centered around the mouth and throat such as slurred speech, difficulty swallowing, and difficulty breathing [3]. Early symptoms of spinal onset ALS include progressive muscle weakness and/or stiffness, muscle spasms, and increased reflexes in the upper or lower extremities. These symptoms are not unique to ALS. In Nancine’s case, her early symptoms mimicked asthma and lung disease. For other patients, early symptoms may imitate a pinched nerve or even a simple lack of exercise [4].

Approximately 10% of cases are hereditary (familial ALS) and the other 90% are considered sporadic, meaning the individual has no known family history of the disorder [5]. For an estimated 30-40% of individuals with familial ALS and most individuals with sporadic ALS, the underlying causes for their disease remain unidentified [6]. Given the uncertainty surrounding ALS, the road to diagnosis is often long and imprecise. In the early stages of ALS, the symptoms tend to mimic other diseases. For instance, Nancine was misdiagnosed with asthma and lung disease before finally being diagnosed with ALS. Additionally, ALS does not show up on scans such as MRI or CT scans. While progress has been made finding cerebrospinal fluid, plasma, serum, urine, and saliva biomarkers for ALS, these body fluid tests are not yet capable of reliably identifying ALS [7]. Other neurological conditions such as spinal cord or nerve root syndromes must be ruled out before diagnosing ALS [4]. By the time characteristic neurological symptoms are noticeable and the primary care physician refers the patient to an appropriate specialist, the motor neurons have already experienced significant damage, as in Nancine’s case. Currently, it takes an average of 11 months to diagnose ALS after symptom onset. This means that people with ALS miss nearly a year of potentially life extending treatment leaving physicians with few options for patients but supportive therapies [4]. 

El Escorial and Awaji Diagnostic Criteria

In 1998, the World Federation of Neurology introduced the revised El Escorial Criteria (rEEC) for the diagnosis of ALS, especially in the absence of any family history of the disorder. This established the following criteria for diagnosing ALS and determining eligibility for clinical trials [8]:

1. Signs of lower motor neuron degeneration by clinical examination (observations from a doctor), electrophysiological examination (testing of the electrical activity in the muscles), or neuropathologic examination (inspection of physical body tissues in a laboratory), including but not limited to: weakened muscles in the arms and/or legs, muscle twitching, foot drop, and loss of muscle tone.

2. Signs of upper motor neuron degeneration by clinical examination, including but not limited to: increased reflexes, challenges with balance and coordination (often mistaken for clumsiness), stiffness of movements, and the presence of the Babinski reflex (when the person’s heel is gently stroked, their big toe points upwards and the other toes fan out–which is not typically present in humans over the age of two).

3. Progressive spread of symptoms within a region or to other regions 

Along with the absence of:

1. Evidence of other disease processes that may explain the upper and lower motor neuron degeneration based on pathology or electrophysiological testing.

2. Evidence of other disease processes based on neuroimaging (such as MRI).

Based on these criteria, the diagnosis falls into one of the following categories of certainty [8]: 

1. Clinically Definite ALS: Clinical evidence of upper and lower motor neuron signs in the bulbar region and at least two spinal regions OR clinical evidence of upper and lower motor neuron signs in three spinal regions

2. Clinically Probable ALS: Clinical evidence of upper and lower motor neuron signs in at least two regions. Some upper motor neuron signs must be rostral to (above) the lower motor neuron signs.

3. Clinically Probable ALS–Laboratory supported: Clinical evidence of upper and lower motor neuron signs in one region along with EMG evidence of lower motor neuron signs in at least two regions OR clinical evidence of only upper motor neuron signs in one region along with EMG evidence of lower motor neuron signs in at least two regions.

4. Clinically Possible ALS: Clinical evidence of upper and lower motor neuron signs in one region OR upper motor neuron signs in two or more regions OR lower motor neuron signs are rostral to upper motor neuron signs.

Most clinical trials for ALS only include participants with “definite” or “probable” ALS [9], but the revised criteria were so restrictive that most participants in clinical trials had progressed significantly in the disease before being eligible for treatment. Most ALS trials that used the rEEC criteria for participation did not demonstrate significant benefits. This may have been because the participants’ nervous systems had already suffered too much irreversible damage before involvement in the trials [1].

In 2008, a consensus meeting gave rise to the Awaji criteria, which built on rEEC to allow for earlier diagnosis of ALS [10]. The Awaji criteria put equal weight on clinical and electrophysiological lower motor neuron signs (listed above) [9], and expanded the list of electrophysiological signs of ALS to include fasciculation potentials [9, 10]. This allowed for more participants to enter into ALS trials earlier on in the disease’s progression. A study conducted in 2009 reported differences in sensitivity–how often the test correctly identifies people who have the disease (true positives)–between the revised El Escorial criteria and the Awaji algorithm. For definite ALS, the Awaji algorithm resulted in 95% sensitivity compared to 18% for the rEEC. The improvement is especially significant for patients with bulbar onset ALS–reflected by an increase in sensitivity from 38% to 87% for the group of participants with bulbar onset. This is because they are less likely to display symptoms in multiple regions but more likely to have fast disease progression [11].

The ALS Diagnostic Index

A new ALS diagnostic index (ALSDI), developed in 2019, incorporates an electrophysiological technique called transcranial magnetic stimulation (TMS) to identify upper motor neuron damage; initial testing demonstrated promising results [2]. TMS assesses upper motor neuron function by placing an electromagnetic coil on the surface of the skull above the brain’s motor cortex which is where upper motor neurons originate [1]. TMS directly stimulates upper motor neurons and measures the resulting motor evoked potentials (messages sent from the brain to the muscles via the spinal cord). TMS allows for the identification of upper motor neuron decline before the patient presents with clinical symptoms. This is a huge advancement in ALS diagnosis because it allows patients to potentially begin treatment before the onset of upper motor neuron symptoms. Starting treatment early could delay the onset of such symptoms and therefore improve quality of life.  

The ALSDI also takes into account age, location of onset, muscle strength, and disease duration. In the test trial of the ALSDI, it demonstrated diagnostic accuracy only 2% higher than the Awaji criteria. But out of 133 patients initially characterized as not having ALS based on the Awaji criteria, 29% were correctly identified to have ALS based on the ALSDI criteria, indicating a potential for earlier diagnosis using the ALSDI. Additionally, 58% of the test subjects who did not have ALS had conditions that are traditionally hard to differentiate from ALS, but the ALSDI reliably identified these subjects as not having ALS. While the ALSDI has great potential as a diagnostic tool, it is important to note that the threshold tracking TMS technique incorporated into the ALSDI requires technology which is not yet commercially available. Additionally, the technique requires specific expertise, which may limit widespread accessibility.

Available Treatments

The FDA has approved two drugs so far that slow the progression of ALS: Rilutek (riluzole) and Radicava™ (edaravone). Riluzole can extend life expectancy by three to five months. Scientists suspect that riluzole blocks the release of glutamate–a neurotransmitter that, in excess, can damage neurons. Edaravone, which the FDA approved for the treatment of ALS in May 2017, seems to work as a free radical scavenger in the central nervous system. Free radical scavengers are better known as antioxidants; they help the body to get rid of excess radical species such as high energy oxygen and nitrogen molecules  which damage cells by increasing oxidative stress. Further research must occur to verify the proposed mechanism for both riluzole and edaravone. According to two recent studies, edaravone slows disease progression by an impressive 33% which resulted in nearly doubling the median lifespan after ALS onset compared to a placebo [12]. Given that edaravone appears to prolong life by more than two years, one may think that everyone with ALS would take it, but currently edaravone is only used to treat a small subset of people with ALS who fit the specific criteria detailed below [13]:

1. Diagnosis of definite or probable ALS based on the Awaji criteria.

2. Ability to perform most daily activities.

3. Normal respiratory function.

4. Disease progression of 2 years or less.

Edaravone is less effective for patients further on in disease progression, so these criteria aim to include only those who are most likely to benefit from the treatment. These parameters exclude many patients, especially patients with bulbar onset ALS. Additionally, by the time someone fits the criteria for probable or definite ALS, they often no longer fit the other criteria (daily function, respiratory function, and disease progression.) If clinicians and pharmaceutical companies implement a diagnostic tool that allows for earlier diagnosis, it could significantly improve outcomes for patients who would not fit the current criteria. Specifically, the ability to detect upper motor neuron distress early on in disease progression through TMS (included in the ALSDI) could allow for more diagnoses of probable or definite ALS before the disease has progressed beyond the window for treatment.

Diagnostic criteria are certainly not the only aspect of ALS diagnosis and treatment that need to improve. For example, if more physicians knew the signs of ALS and knew to refer patients to a neurologist, people with ALS would be diagnosed sooner on average. Nevertheless, improved diagnostic indexes such as the ALSDI offer much-needed hope in the ongoing fight against ALS.

References

[1]. Lacomis, D., & Gooch, C. (2019). Upper motor neuron assessment and early diagnosis in ALS: Getting it right the first time. 92(6), 255–256. 

https://doi.org/doi:10.1212/WNL.0000000000006867 

[2]. Geevasinga, N., Howells, J., Menon, P., van den Bos, M., Shibuya, K., Matamala, J., Park, S., Byth, K., Kiernan, M., & Vucic, S. (2019). Amyotrophic lateral sclerosis diagnostic index: Toward a personalized diagnosis of ALS. 92(6), e536–e547. https://doi.org/doi:10.1212/WNL.0000000000006876 

[3]. Hwang, W.-J., Huang, K., & Huang, J.-S. (2019). Amyotrophic lateral sclerosis presenting as the temporomandibular disorder: A case report and literature review. 37(3), 196–200. https://doi.org/doi:10.1080/08869634.2017.1407117 

[4]. Nzwalo, H., de Abreu, D., Swash, M., Pinto, S., & de Carvalho, M. (2014). Delayed diagnosis in ALS: The problem continues. 343(1), 173–175. https://doi.org/doi:https://doi-org.libproxy.temple.edu/10.1016/j.jns.2014.06.003 

[5]. Walczak, J., Dębska-Vielhaber, G., Vielhaber, S., Szymański, J., Charzyńska, A., Duszyński, J., & Szczepanowska, J. (2019). Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics. 33(3), 4388–4403. 

https://doi.org/doi:10.1096/fj.201801843R 

[6]. ALS Association. (n.d.). Genetic Testing for ALS. Understanding ALS. https://www.als.org/understanding-als/who-gets-als/genetic-testing 

[7]. Vu, L. T., & Bowser, R. (2017). Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 14(1), 119–134. 

https://doi.org/10.1007/s13311-016-0503-x 

[8]. Brooks, B. R., Miller, R. G., Swash, M., & Munsat, T. L. (2000). El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. 1(5), 293–299. https://doi.org/doi:10.1080/146608200300079536 

[9]. Boekestein, W., Kleine, B., G, H., Schelhaas, H., & Zwarts, M. (2010). Sensitivity and specificity of the ‘Awaji’’ electrodiagnostic criteria for amyotrophic lateral sclerosis: retrospective comparison of the Awaji and revised El Escorial criteria for ALS’ (Vol. 11, pp. 497–501).

https://www-tandfonline-com.libproxy.temple.edu/doi/pdf/10.3109/17482961003777462

[10]. Costa, J., Swash, M., & de Carvalho, M. (2012). Awaji Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis: A Systematic Review. 69(11), 1410–1416. https://doi.org/doi:10.1001/archneurol.2012.254 

[11]. Carvalho, M. D., & Swash, M. (2009). Awaji diagnostic algorithm increases sensitivity of El Escorial criteria for ALS diagnosis. 10(1), 53–57. 

https://doi.org/doi:10.1080/17482960802521126 

[12]. Okada, M., Yamashita, S., Ueyama, H., Ishizaki, M., Maeda, Y., & Ando, Y. (2018).  Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis. 11, 11–14. https://doi.org/doi:https://doi.org/10.1016/j.ensci.2018.05.001

[13]. Premera Blue Cross. (n.d.). MEDICAL POLICY – 5.01.578. Radicava® (edaravone).

https://www.premera.com/medicalpolicies/5.01.578.pdf