Defining pre-symptomatic amyotrophic lateral sclerosis

ALS: Disease vs. Clinical Syndrome

The clinical syndrome of ALS is easily recognized based on a history of progressive (yet painless) weakness, along with evidence of both upper and lower motor neuron signs in the same body region. But the underlying disease, by which is meant the presence of some underlying biological (e.g. molecular, cellular, or systems-level) process that eventually leads to the clinical syndrome, almost certainly begins before the clinical syndrome emerges. Such a paradigm is well recognized in cancer, infectious disease and even other neurodegenerative diseases such as Alzheimer’s ^31–34, Parkinson’s ^35–37 and Huntington’s disease ^{38, 39}. As such, it is possible to recognize both a pre-symptomatic and a symptomatic phase of disease in ALS (elaborated below). As a consequence of recognizing the distinction between ALS as a disease process (i.e. the pathobiology that underlies the degeneration of upper and lower motor neurons) and ALS as a clinical syndrome (i.e. the overt clinical syndrome characterized by progressive painless weakness with both upper motor neuron and lower motor neuron signs on physical examination), it becomes necessary to differentiate the onset of the underlying disease from the onset of symptoms. The El Escorial criteria (original and revised ^{40, 41}) provide a definition of onset (without explicitly distinguishing ‘disease’ from ‘clinical syndrome’) as the “time of first subjective symptom noticed by the patient which later is confirmed by examination”; the language used by the authors of these criteria implicitly reference the emergence of the clinical syndrome, but are silent on the question of when the disease process begins. Similarly, most clinical trials operationally specify the initial symptom to be weakness (excluding ‘softer’ symptoms such as fasciculations). By contrast, there has been relatively little discussion in the literature about an operational definition of the onset of disease ^{1, 2, 42}

Risk for ALS: Genetic and Environmental Factors

In at least some individuals the pre-symptomatic phase of disease may be preceded by a period during which the individual is at an elevated risk of disease. For those with a genetic risk factor (e.g. an SOD1 mutation or a C9orf72 repeat expansion), for instance, this period of elevated risk may begin very early in life. For those in whom disease is caused by some environmental exposure(s) ^13–18, for example, the period of increased risk of disease begins only after the relevant exposure. This model would also accommodate the possibility that multiple risk factors (e.g. genetic risk(s) combined with some environmental exposure(s)) are required in order to develop disease ^{43, 44}. In such a scenario, one’s baseline risk might be elevated due to genetic susceptibility, then further increased at some point in one’s lifetime by environmental exposure(s). It is recognized that the causal relationship between environmental exposures and ALS is not yet well-defined, but the example of elevated risk for disease based on some environmental (non-genetic) factor is used primarily to clarify that the conceptual model proposed is, at least in theory, relevant beyond genetic forms of ALS.

Phases of Disease: Pre-Symptomatic vs. Symptomatic

As noted above, we view the disease ALS as being characterized by two phases – a pre-symptomatic phase, followed by a symptomatic phase. The transition from the former to the latter is marked by the emergence of subjective symptoms, and/or objective motor (clinical or electromyographic) or cognitive/behavioral signs that a trained evaluator would reasonably interpret as unequivocal evidence of overt disease. This operational definition of the onset of clinically manifest disease builds upon that proposed by the El Escorial criteria (“time of first subjective symptom noticed by the patient which later is confirmed by examination”), but the distinction between symptoms and signs is purposefully blurred. Either may come first, depending on a complex interplay of factors—for example, the degree to which an individual is physically self-aware and observant; whether the person may be in denial (i.e. neglecting or ignoring symptoms, even if significant); whether the person is enrolled in a pre-symptomatic research study (in which case subtle clinical signs might be observed before the study participant notices any symptom); whether the earliest manifestations of disease are motor or cognitive/behavioral (e.g. if the earliest symptoms include loss of insight, then reporting may be delayed especially in the absence of a reliable informant); etc. It is important to recognize that someone who develops ALS and then FTD may be ‘symptomatic’ for ALS but ‘pre-symptomatic’ for FTD, and vice versa for someone who develops FTD and then ALS.

Stages of Pre-Symptomatic Disease: Pre-Manifest vs. Prodromal

Within the symptomatic phase of disease, different clinical stages based on progression and severity are already recognized ^{45, 46}. These should not be conflated with the more speculative concept of pathological staging, which is currently necessarily based on post mortem histology ⁴⁷. Similarly, for the pre-symptomatic phase, we find it helpful to recognize two stages – a pre-manifest stage, followed by a prodromal stage.

The pre-manifest stage is defined as the period from disease onset to the emergence of the earliest clinical manifestation of disease--namely, the first appearance of possible (or non-specific) symptoms/signs. As explained below, this stage of disease can, by definition, be observed only through biomarker evidence of disease. Such biomarkers may reflect underlying molecular or cellular perturbations or relatively successful compensation, for example at a systems-level.

Immediately following the pre-manifest stage, the prodromal stage begins with the possible symptoms/signs and ends with the emergence of definite symptoms/signs that reflect unequivocal development of symptomatic disease and may reflect a stage of decompensation for underlying molecular, cellular or network perturbations. The motivation for differentiating these two stages of pre-symptomatic disease derives from experience of following a large cohort of individuals at genetic-risk for ALS and observing phenoconversion in over a dozen individuals so far: Sometimes the earliest possible clinical manifestations of disease (e.g. isolated denervation of thoracic paraspinal muscles) are non-specific and difficult to interpret; and it is not until later when unequivocal weakness appears, that the emergence of clinically manifest disease can be declared with confidence. As a result, simple use of the term ‘pre-symptomatic’ seems inadequate for characterizing these individuals, as it does not adequately distinguish those in whom there are no clinical symptoms or signs whatsoever (i.e. pre-manifest) and those in whom there are subtle clinical symptoms or signs, but which are insufficiently specific to permit a confident conclusion that manifest disease has emerged (i.e. prodromal). It is recognized that these two phases of pre-symptomatic disease are most easily recognized and characterized in the population at genetic risk for disease. Although a similar model likely applies to sporadic forms of ALS, it is far from clear that people without genetic susceptibility should be classified as having pre-symptomatic disease based solely on the presence of non-specific symptoms or signs such as fasciculation.