Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper (UMN) and lower motor neurons (LMN). The UMNs are bilaterally localized in the motor cortex, which is in the frontal lobe located anterior to the central sulcus and is functionally involved in planning, controlling and execution of voluntary movements. The motor cortex has a topographic organization, also known as the homunculus, in which different sections control voluntary movement of specific body regions. From the UMN axons descend through the corticospinal tract down into the brain stem and spinal cord where they make functional connections with LMNs. In turn, the LMNs are connected via axons to muscles. Via neurotransmission the LMNs can activate muscles, thereby facilitating contraction and thus movement. The LMNs are located in nuclei in the brain stem and along the length of the spinal cord in the ventral horn. The LMNs in the brain stem predominantly control the muscles of the head, face and mouth area, whereas the LMNs located in the cervical part of the spinal cord innervate muscles in the arms and hands, those in the thoracic spinal cord control the torso and also respiratory muscles and lastly, the caudal (or lumbar/lumbosacral) part innervates the lower limbs (Brown and Al-Chalabi, 2017, Feldman et al., 2022) This subdivision of the body into four regions (bulbar, cervical, thoracic and lumbar) has practical applications in the diagnostic process as will become evident later in this chapter.

Clinically, the degeneration of UMNs and LMNs lead to different signs. The loss of UMN results in weakness, spasticity, hypertonia and pathologically brisk reflexes (hyperreflexia, clonus, pseudobulbar reflexes, Babinski’s and Hoffmann sign), whereas LMN loss is characterized by marked atrophy, fasciculations (and cramps), hypotonia and reduced or absent reflexes (Brown and Al-Chalabi, 2017, Feldman et al., 2022, van Es et al., 2017).

The first symptoms and signs therefore correspond with the location of disease onset within the motor system. At presentation there can be variable degrees of UMN and/or LMN involvement and the initial manifestation can be in any voluntary muscle. As the disease progresses, additional areas of the motor system become affected, leading to the emergence UMN and LMN signs in other regions of the body as well. The rate of progression and order of spread are also variable. As a result, the clinical presentation of ALS is highly heterogeneous and therefore challenging to diagnose (Brown and Al-Chalabi, 2017, Feldman et al., 2022, van Es et al., 2017).

Particularly, because there is no single diagnostic test by which ALS can be diagnosed. ALS needs to distinguished from other diseases affecting motor neurons (MNs) as well as from separate conditions that may cause similar symptoms (mimics). Therefore, ALS is a diagnosis made by exclusion. Further adding to the complexity is the fact that neurodegeneration in ALS may not be limited to MNs. In up to 50% of ALS patients there may also be involvement of cortical neurons in the frontal and/or temporal lobes, leading to behavioral changes and cognitive deficits that mainly affect language and executive function. These behavioral changes and cognitive deficits are commonly seen in frontotemporal dementia (FTD). Indeed, the current consensus is that ALS and FTD are closely linked disorders that may even form the extremes of a clinical continuum of one and the same disease. Patients may therefore also present with FTD and only develop motor neuron involvement over time (Andersen, 2013, Burrell et al., 2016).

The objective of this chapter is provide guidance on how to diagnose ALS by describing the most common presentations and for each of these the relevant mimics and disorders that should be considered. This chapter also deals with the epidemiology, genetics and underlying pathology of ALS, which to some degree accounts for the underlying factors driving in the heterogeneity of ALS phenotypes.