What’s in a name?

The diagnostic challenges in motor neuron disease are deceptively simple. A definitive diagnosis of amyotrophic lateral sclerosis (ALS) requires a combination of progressive upper and lower motor neuron features.¹ The diagnostic label of primary lateral sclerosis (PLS) describes patients with exclusively upper motor neuron signs while progressive muscular atrophy (PMA) describes those with only lower motor neuron involvement.² Although these diagnostic labels suggest a match to affected populations of motor neurons, there are few, if any, other neurodegenerative diseases where the phenotypic expression of the disease varies as markedly as that observed in the spectrum of ALS and the related motor neuron disorders.³ Clinical and pathologic features beyond the motor system are almost universal in all the clinical forms of the disease. The obstacles we currently confront in assigning the few available diagnostic labels to identify individual disease entities within the large spectrum of motor neuron disease may be the most serious impediment to our understanding and treatment of these diseases. On the other hand, these clinical phenotypes are well known, may be easily recognizable, and are hallowed in the history of neurology.

In this issue, Gordon et al.⁴ present a retrospective analysis of patients presenting with predominantly or exclusively upper motor neuron signs. They report a follow-up examination of 39 patients presenting with a PLS-like syndrome, 29 fulfilling initial criteria for PLS. Of these, 13 developed a relatively benign UMN predominant ALS syndrome, with long survival, 16 continued to show a pure UMN syndrome compatible with PLS a mean of 8.7 years after presentation. Recognition of pure PLS was reliable after 4 years observation, including repeat EMG evaluation. Based on the progression of clinical signs and the outcome, they propose criteria for defining PLS vs upper motor neuron predominant ALS (UMN-ALS). Their attempt to categorize subgroups within the spectrum of ALS/PLS is a critical step in facilitating clinical research in motor neuron disease. The diagnosis of this disorder is currently a clinical matter. We must consider the possibility that different motor neuron disease presentations, currently included in the unifying diagnosis of ALS, have different etiologies or at least different modifying factors, whether genetic or environmental. The number of possible pathophysiologic mechanisms associated with motor neuron degeneration in ALS is striking.⁵ Despite this we often approach clinical treatment trials, using a single therapeutic agent, on the assumption that all affected patients have the same underlying etiology. If different mechanisms are responsible for different presentations the range of clinical features in the population of patients we test may itself preclude detection of a benefit. In addition, interactions between different mechanisms of motor neuron death may lead to varying and inconsistent patterns of motor neuron degeneration resulting in a mixed population of clinical phenotypes and differing patterns of response to any therapeutic agent. These mechanisms might be in part genetic and in part environmental further confounding our ability to identify a subgroup of patients with a more homogeneous presentation.

How can we simultaneously account for near complete bulbar sparing and aggressive limb wasting with the same pathologic process that results in profound bulbar compromise and minimal limb involvement? How can a patient with an indolent form of subtle upper and lower motor neuron degeneration be affected by exactly the same pathologic process as those less fortunate patients who progress aggressively despite maximal supportive and adjunctive therapies? The lower motor neurons in the patients with UMN-ALS described by Gordon et al.⁴ are vulnerable, but remain less affected than in patients with more virulent forms of progressive ALS. In PMA syndromes the lower motor neurons are selectively vulnerable and can decline precipitously or, in other patients, over a prolonged course without concomitant upper motor involvement. Cognitive impairment is frequent in ALS but is not universal. Addressing this heterogeneous population of “patients with ALS” under a single diagnostic label can be detrimental to the well-being of the individual, given an incorrect expectation of progressive disability, and clinical heterogeneity may mask drug effects in clinical trials. If distinct pathologic entities are responsible for different disease presentations then our best attempts to monotherapy will continue to be fruitless as only subsets of patient groups in a heterogeneous population may respond.

There are lumpers and splitters in most neurodegenerative disease states. In the area of motor neuron disease, however, our persistence in lumping patients under a single diagnostic category may be the greatest obstacle in understanding any one group of affected patients. Developing a single effective drug treatment to arrest the underlying motor neuron degeneration in all patients with any motor neuron degeneration may be both optimistic and unlikely. Gordon et al. have initiated a critical process of categorizing subgroups of affected patients, through a strategy of addressing an extreme and readily identified population of patients with PLS. This process must now become the first of many steps to categorize other subgroups, such as patients with indolent forms of motor neuron disease; those who present with rapidly aggressive forms; those with focal or monomelic forms; those with lower motor predominant presentations; patients with ALS associated with frontotemporal dementia; and the spectrum of generalized motor neuron degeneration with asymmetric or multifocal presentations. The search for genes and for environmental triggers will be more likely to be rewarded with such splitting.

Advances in arresting motor neuron degeneration may come not only from the laboratory but also from the clinic. Definition of clinicopathologic syndromes in affected patients is among our most important challenges that cannot be ignored.