The motor neurone diseases

Abstract

Motor neurone disease (MND) refers to a spectrum of disorders resulting from degeneration of the upper (UMN) and/or lower motor neurone (LMN) population. Currently, the diagnostic distinctions within this spectrum of MND are dependent upon clinical and electrophysiological evidence of UMN versus LMN involvement as well as the distribution of clinical signs along the neuraxis (Table 2.1). The contrast between bulbar and limb predominance, UMN versus LMN predominance, rapid versus slow progression and the extent of cognitive involvement can be striking. Recently, an increasing number of genetic abnormalities have been identified, which further define specific inherited variants of MND and serve as a diagnostic standard in those specific clinical settings. In addition, historically there have been geographical regions identified worldwide where the incidence rates of MND subtypes are disproportionately high, implicating a distinct potential aetiology in those patients.The clinical variability underlying the MND disorders has been a challenge in identifying therapeutic strategies in heterogeneous treatment groups. Distinct aetiologies have been proposed, including genetic, biochemical, metabolic, cytoskeletal, and inflammatory mechanisms. These may serve as either a primary or secondary processes underlying the disparate clinical presentations.The term amyotrophic lateral sclerosis (ALS) and MND are often used synonymously. However, MND is more accurately thought of as a category of disease presentations encompassing a great variety of clinical phenotypes. In the UK and in some European countries, the term MND is synonymous with ALS. In the United States and Canada, however, MND refers to a more general spectrum of disorders involving degeneration of motor neurones. ALS, by contrast, is limited to those clinical syndromes where both UMN and LMN clinical pathology exists along the neuraxis, often affecting bulbar and limb regions. Historically, there have been four categories of ALS clinical variants recognized despite the solitary ALS nomenclature. 1. The classical sporadic variant as originally described by Charcot (10).2. A familial form of ALS defined by an increasing number of mutations affecting several genes (see Tables 2.2, 2.3).3. A geographical variant of ALS restricted to an area in the western Pacific implicating an environmental aetiology.4. Anatomical variants of ALS where clinical pathology is restricted to either bulbar or limb involvement (predominantly). Patients affected solely with bulbar pathology are also often referred as having progressive bulbar palsy (also known as progressive bulbar atrophy), whereas patients affected with bulbar predominant symptoms are referred to as bulbar ALS.Furthermore, our traditional view of ALS as a disorder restricted to the motor system has been greatly modified by recognition of comorbid syndromes of frontotemporal dysfunction in up to 30–50% of patients. As discussed elsewhere in this text, patients with ALS are now identified as having primarily cognitive or behavioural pathology versus primary motor symptoms and more subtle cognitive involvement. ALS is therefore best viewed a multisystem disorder in which the motor system is affected early and the patient's symptoms are progressive. Multisystem involvement is supported by the range of concurrent cognitive, behavioural, or dysexecutive symptoms. In a subgroup, a more florid dementia consistent with a frontotemporal dementia will be evident (see subsequent chapters).The heterogeneity of clinical presentation in patients diagnosed with ‘ALS’ has presented a great challenge to the discovery of underlying mechanisms; it remains unclear if this clinical spectrum reflects disparate aetiologies with distinct pathogenesis or multiple presentations of a single pathogenic mechanism.