Chapter 6: Amyotrophic Lateral Sclerosis

INTRODUCTION

The motor neuron diseases (MNDs) are categorized by their pathological affinity for the voluntary motor system including anterior horn cells, certain motor cranial nerve nuclei, and corticospinal/bulbar tracts. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is the most notorious of these disorders. The boundaries of what is and what is not ALS, particularly in the context of early diagnosis of individual patients, remain imprecise. In this Chapter, in an attempt to distinguish ALS from other MNDs, we consider ALS to be a disorder that has the following characteristics: (1) the clinical manifestations are dominated by signs attributable to voluntary motor system dysfunction, (2) the disease progresses rapidly both within and between different body regions, (3) that life expectancy is <5 years from clinical onset in the vast majority of cases, (4) and that no other etiology can be identified.

Despite its characterization as a motor system degeneration, ALS is best conceptualized as a multisystem disorder.¹ This perspective is reinforced by both a clinical and pathological overlap between ALS and frontotemporal lobar degeneration (FTLD) (pathological) and frontotemporal dementia (clinical).² Consequently, ALS is more correctly considered as a disorder in which dysfunction of the voluntary motor system involvement is the dominant source of morbidity (in the majority of cases) but in which involvement of other neurological systems at times clinically, and more commonly pathologically, develops.

The uncertain etiology of sporadic ALS (sALS) and the increasingly complex biology of ALS contribute to a lack of coherence in ALS nosology. This confusion applies to both historical and contemporary perspectives. In 1849 and 1850, respectively, Duchenne and Aran described progressive muscular atrophy (PMA), a disorder they believed to be of muscular origin. PMA has been long recognized however, to result from anterior horn cell degeneration.³ In 1860, Duchenne first described a syndrome of progressive dysphagia and dysarthria and coined the term progressive bulbar palsy (PBP).³ In 1874, Charcot and Cruveilhier recognized that corticospinal tracts and anterior horn cells were often affected concomitantly. Their description serves as the basis for our current construct of ALS.³ In the next year, Erb described primary lateral sclerosis (PLS), a progressive disorder of corticospinal tracts, without (at least initially) evidence of muscle atrophy, fasciculation, or weakness.³ ALS, PMA, PBP, and PLS are accepted by most, but not all neurologists as interrelated entities. PMA and PLS are clinically defined by the type of motor neuron affected. PBP on the other hand, is defined by site of disease onset, regardless of the type of motor neuron involved. Although survival in PMA and particularly PLS will on average exceed that of ALS, there is considerable overlap.^4–10 Survival in ALS does not differ significantly between different disease categories as described by the El Escorial criteria (EEC) (see below) including the original EEC-suspected category that is synonymous with PMA, that is an exclusively lower motor neuron (LMN) presentation.^...