Diagnosis of ALS

Neuroimaging
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Many advances in the research field aim towards finding an effective diagnostic method for ALS.

1. Introduction
Amyotrophic lateral sclerosis or Lou Gehrig ’s disease is a neurodegenerative disorder that affects the motor system in affected individuals. Its symptoms include muscle weakness, spasms and atrophy amongst others and patients generally begin displaying these between the ages of 40 – 65 or so. ALS progresses quite rapidly: about half of all diagnosed patients die about 30 months after symptoms first begin manifesting[1]. Because of this, it is crucial that individuals are diagnosed in the early stages so that proper care and treatment can be provided. In the present time, there is no specific test or examination that will guarantee a definite diagnosis; however, medical practitioners rely on a set of certain characteristics or signs to reach an accurate diagnosis[1]. There is no single test that will diagnose an individual with ALS; however, there are many different characteristics of this disease that can be identified using tests and therefore point practitioners in the right direction. El Escorial Criteria in particular mentions the specific characteristics and features that need to be displayed in an individual for a proper ALS diagnosis[1]; although they are not exclusive. It classifies diagnosis into four different categories depending on severity of upper as well as lower motor neuron degeneration (which must not be explained by the presence another neurological disorder)[1]. Physicians use a combination of a few methods such as electromyography and neuroimaging[2],[3] to identify UMN and LMN which is the most prominent feature in neurodegenerative disorders and therefore ALS. Furthermore, current research is looking into whole-brain magnetic resonance spectroscopic imaging (MRSI) as a source of determining disability levels in ALS in the future[4].

El Escorial Criteria

El Escorial Criteria
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Breakdown of El Escorial Criteria

Upper and Lower Motor Neuron Degeneration

Upper and Lower Motor Neuron Degeneration
ALS is characterized as a disease that mainly causes damage to upper and lower motor neurons[5]. Upper motor neurons originate in the brain and transmit information to lower motor neurons. In turn, lower motor neurons will connect the spinal cord to muscles in the human body. As their name suggests, these are crucial for motor control in individuals, and any deterioration to these will cause issues in the motor system and severe damage may even cause paralysis. Overall, the damage of neurons in patients with ALS occurs mainly in the spinal cord, the primary motor cortex and the brain stem; therefore making it an issue where both lower and upper motor neurons are affected[6]; as previously mentioned, this will ultimately result in muscle paralysis. Studies have discovered that degeneration of the neurons in the anterior horn will inevitably lead to denervation, or disruption of nerves. Consequently, motor neurons in both the lateral as well as anterior corticospinal tracts begin to stiffen, and are eventually substituted by gliosis, potentially resulting in a glial scar[6]. The exact pathogenesis behind the explained motor degeneration is not exactly known by scientists, however it is speculated to be the result of a multiple factors, specifically, genetic factors, excessive glutamate at the synapse, oxidative stress, defective axonal transport, dysfunction of the mitochondria, the aggregation of proteins as well as neurofilaments, defects in signaling pathways amongst other factors[6]. Significant diagnostic techniques would include any methods that may identify these previously mentioned factors, but the most important component to diagnosis would be an efficient determination of upper and/or lower motor neuron damage.

Breakdown and Description

El Escorial World Federation of Neurology describes the criteria needed for an individual to be classified with amyotrophic lateral sclerosis. El Escorial Criteria has been in used for many decades in the medical community, but only recently it was revised to further improve its criteria[7]. The updated version describes four categories of possible diagnosis in terms of the degree of disease: clinically possible ALS, clinically probable ALS (with the additional option of laboratory supported), and finally clinically definite ALS[7].
A diagnosis of clinically possible ALS would require a patient to display a combination of upper and lower motor neuron degeneration in one area of the body, upper motor neuron degeneration in two regions or lower motor neuron above upper motor neuron damage. For a patient to be classified as having clinically probable ALS that is laboratory supported, they must display upper and lower motor neuron degeneration in one body region[7]. An alternative to this is undergoing electromyography and showing denervation in at least 2 limbs. If a patient is displaying upper and motor neuron in two areas, they are classified with clinically probably ALS; and finally, in clinically definite ALS, a patient must have upper and motor neuron damage in at least three regions of their body[7]. A crucial component of ALS diagnosis is ruling out any other possible diseases which may mimic ALS due to similarity in symptoms.

Diagnostic Tests

Electromyography (EMG)
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EMGs are used to determine lower motor neuron degeneration

Electromyography

Electromyography (EMG) is a vital method to determine any type of lower motor neuron damage[2]; therefore it is extensively used in the medical field as a way to diagnose motor neuron diseases such as ALS. It does this by identifying that affected as well as non-affected regions in ALS patients suffer from muscle denervation[2]. EMG has the capability of identifying lower motor neurons in healthy muscles and therefore can identify that a loss of motor neurons will result in muscle weakness[2]. It is important to note that the revised version of El Escorial Criteria has caused much controversy, as it states that EMG alone is not sufficient to conclude lower motor neuron damage in a region of an affected patient’s body[7].

Neurophysiological Tests

Neurophysiological tests are also useful when diagnosing ALS, as they can determine both lower and upper motor neuron degeneration; an important marker for ALS1. For example, a new technique known as MUNIX (motor unit number index) is used in patients as a means to evaluate and asses the loss of motor neurons[8]. Research shows that this promising method poses certain advantages against other: it is effectively accepted in subjects undergoing the test[3]. Finally, this method is not as time consuming as others have proven to be in the past[8].

Signs of Hyperreflexia

Just as EMG is used to determine lower motor neuron damage, any sign of hyperreflexia is usually an indicator of degeneration of upper motor neurons[9]. As its name explains, hyperreflexia can be described as the over activity of a reflex[9], such as muscle spasms, twitching and involuntary contractions. Additionally to involuntary muscle movement, ALS patients experiencing hyperreflexia may have an irregular heartbeat, which is something that medical doctors should also detect. Identifying signs of hyperreflexia are equally as important in ALS patients as EMG is, as El Escorial requires the presence of both upper and lower motor neuron damage.

Stages of Disease

Denervation of Muscles
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Denervation of muscles of ALS patients worsens as disease progresses

Number and Characteristics of Stages

There has been determined to be four stages of ALS, where the first three stages are characterized by affected functions of bulbar, upper and lower limbs[10]. The fourth stage is reached once the individual’s respiratory system and deglutition processes are severely impaired, to the point where medical involvement is required[5]. All four stages display muscle wasting and weakness, dysphagia and dysarthria amongst other impediments[5]; however logically the severity of each symptom increases as stages progress. In terms of stage duration, studies have shown that there is an average length of three to seven months during stages 2-4, and it should be noted that stage reversion almost never occurs[10]. These guidelines may be useful when diagnosing patients and determining their current ALs stage.

Determining Stages of ALS in Patients

When determining the stage of disease in an ALS patient, it is mostly done by looking at symptom progression and comparing against previous cases. Symptoms of ALS include: dysphagia, dysarthria, muscle weakness, spams and atrophy, depression and anxiety, dyspnea and sialorrhoea[1]. Logically, the severity of each symptom will naturally worsen as the disease progresses and therefore doctors can classify patients by evaluating these. Early stages of a disease may be characterized by overall muscle weakness and some dysarthria issues for example, while late stages of ALS will unquestionably result in a full body paralysis.

Current research: the future of ALS diagnosis

MRSI tests

N- acetylaspartate is a brain metabolite found within brain tissue and indicates the function of mitochondria[4]. It is found at high levels within the brain and can therefore be easily analyzed and used extensively in research. Studies show that ALS patients seem to have lower than normal levels of NAA within the corticospinal tract. Levels of NAA in ALS patients are found to be consistently lower than those of healthy individuals regardless of the stage or specific disease subtype4; this suggests that future diagnostic strategies could benefit from using NAA as a neuronal marker.
MRSI also found levels of NAA to be correlated with degree of disability amongst patients, such that those with a more severe condition displayed lower levels of NAA on average[4]. Finally, ALS patients were also found to have lower FA and therefore higher MD within the CST4. Overall, the medical field is looking at NAA for its potential in future diagnostic methods for ALS. Measuring NAA levels could facilitate diagnosis of ALS in patients; ideally, a threshold level of NAA should be established, and anything below it should stand out as a risk factor in a patient. Future medical practices could potentially organize a chart correlating degree of disability/stage of disease and levels of N-acetylaspartate and this will surely make ALS diagnosis a simpler and more straightforward process.

Bibliography
1. Kiernan, M., Vuvic, S., Cheah, B., Turner, M., Eisen, A., Hardiman, O., Burrell, J. & Zoing, M. Amyotrophic Lateral Sclerosis. Lancet 377, 942-955 (2011).
2. Krarup, C. Lower motor neuron involvement examined by quantitative electromyography in amyotrophic lateral sclerosis. Clin Neur 122, 414-422 (2011).
3. de Carvalho, M., & Swash, M. Sensitivity of electrophysiological tests for upper and lower motor neuron dysfunction in ALS: A six‐month longitudinal study. Muscle & nerve 41, 208-211 (2010).
4. Stagg, C., Knight, S., Talbot, K., Jenkinson, M., Maudsley, A. & Turner, M. Whole-brain magnetic resonance spectroscopic imaging measures are related to disability in ALS. Neurology 80, 610- 615 (2013).
5. Lehnert, S. et al Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis. ALS Frontotemp Degener 1, 1-7 (2014).
6. Wijesekera, L. C., & Leigh, P. N. Amyotrophic lateral sclerosis. Orphanet J Rare Dis 4, 3 (2009).
7. Douglass, C. P., Kandler, R. H., Shaw, P. J., & McDermott, C. J. An evaluation of neurophysiological criteria used in the diagnosis of motor neuron disease. J Neurol Neurosurg Psychiatry 81, 646-649 (2010).
8. Neuwirth, C., Nandedkar, S., StåLberg, E., & Weber, M. Motor unit number index (MUNIX): a novel neurophysiological technique to follow disease progression in amyotrophic lateral sclerosis. Muscle Nerve 42, 379-384 (2010).
9. D'amico, E. et al. Clinical evolution of pure upper motor neuron disease/dysfunction (PUMMD). Muscle Nerve 47, 28-32 (2013).
10. Balendra, R. et al. Use of clinical staging in amyotrophic lateral sclerosis for phase 3 clinical trials. J Neurol Neurosurg Psychiatry 96, 103-111 (2014).

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