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Epidem iological studies have detected possible associations betw een M ND and previous disturbances to the neurom uscular system. For exam ple, acute in ju ry to muscles and nerves caused by traum a and surgery, and more chronic dam age in curred during hard physical exercise either occupational or sports orientated.

Back and limb traum a (K urtzke & Beebe 1980, Gaw el et al 1983, G allagher & Sanders 1987), "m echanical injuries" (K ondo & T subaki 1981, Chio et al 1991), and experience o f severe electric shocks (Gawel et al 1983, D eapen & H enderson 1986) before onset o f M ND , have all been reported m ore frequently by cases com pared to controls, though other studies have not fo u n d any d ifferen ce in the occurrence o f these factors (A rm on et al 1991(b)). The relationship betw een acute injuries and M ND is unknow n, and does not follow a particular p a tte rn (Chio e ta l 1991) or correspond to the initial site w here M N D m anifests itself (K ondo & T subaki 1981). It could represent a greater vulnerability to traum a because o f p re-clin ical M ND muscle weakness, or in some way predispose to or p recipitate the disease. A lternatively it could sim ply reflect bias recall. N egative results for increased traum a suggest M ND is not a direct consequence o f a m echanical in ju ry (K ondo & T subaki 1981).

G reater incidence o f surgical operations has been docum ented for patients w ith M ND com pared to controls (K urtzke & Beebe 1980), but m any other researchers could not confirm this.

In fav o u r o f M ND being the result of ’w earing out’ the m otor neurones from excessive use, is docum entation showing patients w ith M ND having p articipated m ore intensely in sports activities (Felm us et al 1976, K u rtzke & Beebe 1980), or been em ployed m ore frequently in hard m anual occupations (Provinciali & G iovagnoli 1990, G unnarsson & Palm 1984) com pared to control subjects. The focus o f this theory centres on the fam ous baseball player Lou G ehrig, whose pre-diagnostic perform ance started declining 18 m onths before he retired from the game (K asarskis & Winslow 1989). The use o f pneum atic tools has also been suggested as a possible contributory factor (G allagher & Sanders 1983). H ow ever, again these are not constant findings in other case-control studies (A rm on et al 1991(b), K ondo & T subaki 1981), and th erefo re cannot have a sim ple relationship with MND.

(i) M N D ASSOCIATED WITH O T H ER DISEASES/DISORDERS

O ther N eurological Diseases: C ase-control studies have id entified increased frequency of other neurological diseases in relatives o f patients w ith M N D com pared to controls (Pierce- R u hland & Patten 1981, Deapen & H enderson 1986, A rm on e ta l 1991). D iffe ren t approaches to assessing this area how ever, makes any conclusions im possible. Patients them selves do not appear to su ffe r o ther neurological diseases m ore frequently than control subjects (A rm on et al 1991(c), Leone et al 1987). N evertheless, the occurrence o f dem entia in conjunction with sporadic M ND is increasingly recognised in a small proportion o f su fferers (M yrinathopoulos & Sm ith 1962, Editorial Lancet 1990(c)). There are also case reports o f M ND in patients w ith both P arkinson’s disease and M ultiple Sclerosis (H ader et al 1986, Hudson 1981).

Neoplasms: The discovery that a considerable num ber o f patients w ith M ND had coexisting carcinom a led to the proposal that M ND was attrib u tab le to the carcinom a (Brain et al 1965). T his tren d has been reported elsewhere (Chio et al 1991), but other studies have not confirm ed this relationship (Leone et al 1987, Barron & R odichok 1982, Provinciali & G iovagnoli 1990). M N D in patients w ith lym phom a has been recognised fo r some tim e (Y ounger et al 1991) and the relationship could indicate a common cause (see section on Im m unological Hypothesis). A link betw een inherited colorectal cancer (E ditorial L ancet 1991) and low er m otor neurone degeneration in adults has been postulated (Shaw et al 1991(b)). It rem ains to be seen w hether the location o f the genes responsible for Spinal M uscular A trophies and a specific colorectal cancer to chrom osom e 5q will be significant for other inherited m otor neurone disorders.

T hvroid Diseases: E xophthalm ic goitre can produce sym ptom s th at sim ulate progressive m uscular atrophy w hich resolve a fter partial thyroidectom y (A yer et al 1934). T here are how ever, indications that a history o f thyroid disease may occur in patients w ith M ND m ore o ften than expected by chance (A ppel et al 1986, Chio et al 1991, A rm on et al 1991(c)). The heterogeneity o f antecedent thyroid disease makes it highly unlikely that a causal relationship w ith M N D exists (A rm on et al 1991(c)). Interestingly, there does appear to be a physiological relationship betw een thyrotropin releasing horm one (TR H ) and m otor neurone function (review ed G u ilo ff 1987), which could include an excitatory and "trophic" role. This has led to experim ental treatm ents with T R H using M ND patients, but u n fortunately im provem ent in sym ptom s is slight and transitory (M odarres-Sadeghi et al 1988).

G astro -in testin al Problems: An association betw een gastric disorders or peptic ulceration and M N D has been considered because o f the increased frequency reported in some studies (Chio e ta l 1991, den H artog Jager 1987). This has not been confirm ed elsew here (K ondo 1979), and could be a chance association.

A ny positive relationship betw een M ND and other diseases is tenuous considering that many epidem iological studies have investigated m edical history and found no links (R oelofs-Iverson et al 1984, K u rtzke & Beebe 1980, P ierce-R uhland & Patten 1981). D iffe ren t m ethodology and populations could account for some o f the discrepancies.